Compounds that are S1P modulating agents and/or ATX modulating agents

ABSTRACT

Compounds of formula (I) can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX).

RELATED APPLICATIONS

This application is a 35 U.S.C. §371 national stage filing ofInternational Application No. PCT/US2013/052329, filed on Jul. 26, 2013,which claims the benefit of the filing date of U.S. ProvisionalApplication No. 61/676,692, filed on Jul. 27, 2012, the entire contentsof which are incorporated herein by reference.

TECHNICAL FIELD

This invention relates to compounds that are S1P modulating agentsand/or ATX modulating agents, and methods of making and using suchcompounds.

BACKGROUND

Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokesa variety of cellular responses by stimulation of five members of theendothelial cell differentiation gene (EDG) receptor family. The EDGreceptors are G-protein coupled receptors (GPCRs) and on stimulationpropagate second messenger signals via activation of heterotrimericG-protein alpha (Gα) subunits and beta-gamma (Gβγ) dimers. Ultimately,this S1P-driven signaling results in cell survival, increased cellmigration and, often, mitogenesis. The recent development of agoniststargeting S1P receptors has provided insight regarding the role of thissignaling system in physiologic homeostasis. For example, theimmunomodulating agent, FTY720(2-amino-2-[2-(4-octylphenyl)ethyl]propane 1,3-diol), that followingphosphorylation, is an agonist at 4 of 5 S1P receptors, revealed thataffecting S1P receptor activity influences lymphocyte trafficking.Further, S1P type 1 receptor (S1P₁) antagonists cause leakage of thelung capillary endothelium, which suggests that S1P may be involved inmaintaining the integrity of the endothelial barrier in some tissuebeds. S1P type 4 receptors (S1P₄) are expressed mainly in leukocytes,and specifically S1P₄ mediates immunosuppressive effects of S1P byinhibiting proliferation and secretion of effector cytokines, whileenhancing secretion of the suppressive cytokine IL-10. See, for example,Wang, W. et. al., (2005) FASEB J. 19(12): 1731-3, which is incorporatedby reference in its entirety. S1P type 5 receptors (S1P₅) areexclusively expressed in oligodendrocytes and oligodendrocyte precursorcells (OPCs) and are vital for cell migration. Stimulation of S1P₅inhibits OPC migration, which normally migrate considerable distancesduring brain development. See, for example, Novgorodov, A. et al.,(2007) FASEB J, 21: 1503-1514, which is incorporated by reference in itsentirety.

S1P has been demonstrated to induce many cellular processes, includingthose that result in platelet aggregation, cell proliferation, cellmorphology, tumor-cell invasion, endothelial cell chemotaxis andangiogenesis. For these reasons, S1P receptors are good targets fortherapeutic applications such as wound healing, tumor growth inhibition,and autoimmune diseases.

Sphingosine-1-phosphate signals cells in part via a set of Gprotein-coupled receptors named S1P₁, S1P₂, S1P₃, S1P₄, and S1P₅(formerly EDG1, EDG5, EDG3, EDG6 and EDG8). The EDG receptors areG-protein coupled receptors (GPCRs) and on stimulation propagate secondmessenger signals via activation of heterotrimeric G-protein alpha(G_(α)) subunits and beta-gamma (G_(βγ)) dimers. These receptors share50-55% amino acid sequence identity and cluster with three otherreceptors (LPA₁, LPA₂, and LPA₃ (formerly EDG2, EDG4 and EDG7) for thestructurally related lysophosphatidic acid (LPA).

A conformational shift is induced in the G-Protein Coupled Receptor(GPCR) when the ligand binds to that receptor, causing GDP to bereplaced by GTP on the α-subunit of the associated G-proteins andsubsequent release of the G-proteins into the cytoplasm. The α-subunitthen dissociates from the βγ-subunit and each subunit can then associatewith effector proteins, which activate second messengers leading to acellular response. Eventually the GTP on the G-proteins is hydrolyzed toGDP and the subunits of the G-proteins reassociate with each other andthen with the receptor. Amplification plays a major role in the generalGPCR pathway. The binding of one ligand to one receptor leads to theactivation of many G-proteins, each capable of associating with manyeffector proteins leading to an amplified cellular response.

S1P receptors make good drug targets because individual receptors areboth tissue and response specific. Tissue specificity of the S1Preceptors is desirable because development of an agonist or antagonistselective for one receptor localizes the cellular response to tissuescontaining that receptor, limiting unwanted side effects. Responsespecificity of the S1P receptors is also of importance because it allowsfor the development of agonists or antagonists that initiate or suppresscertain cellular responses without affecting other responses. Forexample, the response specificity of the S1P receptors could allow foran S1P mimetic that initiates platelet aggregation without affectingcell morphology.

Sphingosine-1-phosphate is formed as a metabolite of sphingosine in itsreaction with sphingosine kinase and is stored in abundance in theaggregates of platelets where high levels of sphingosine kinase existand sphingosine lyase is lacking. S1P is released during plateletaggregation, accumulates in serum, and is also found in malignantascites. Reversible biodegradation of S1P most likely proceeds viahydrolysis by ectophosphohydrolases, specifically thesphingosine-1-phosphate phosphohydrolases. Irreversible degradation ofS1P is catalyzed by S1P lyase yielding ethanolamine phosphate andhexadecenal.

Autotaxin (ATX, ENPP2) is a secreted glycoprotein widely present inbiological fluids, including blood, cancer ascites, synovial, pleuraland cerebrospinal fluids, originally isolated from the supernatant ofmelanoma cells as an autocrine motility stimulation factor (Stracke, M.L., et al. Identification, purification, and partial sequence analysisof autotaxin, a novel motility-stimulating protein. J Biol Chem 267,2524-2529 (1992), which is incorporated by reference in its entirety).ATX is encoded by a single gene on human chromosome 8 (mouse chromosome15) whose transcription, regulated by diverse transcription factors(Hoxal3, NFAT-1 and v-jun), results in four alternatively splicedisoforms (α, β, γ, and δ). See, for example, Giganti, A., et al Murineand Human Autotaxin alpha, beta, and gamma Isoforms: Gene organization,tissue distribution and biochemical characterization. J Biol Chem 283,7776-7789 (2008); and van Meeteren, L. A. & Moolenaar, W. H. Regulationand biological activities of the autotaxin-LPA axis. Prog Lipid Res 46,145-160 (2007); Hashimoto, et al, “Identification and BiochemicalCharaterization of a Novel Autotaxin Isoform, ATXδ,” J. of BiochemistryAdvance Access (Oct. 11, 2011); each of which is incorporated byreference in its entirety.

ATX is synthesized as a prepro-enzyme, secreted into the extracellularspace after the proteolytic removal of its N-terminal signal peptide(Jansen, S., el al Proteolytic maturation and activatio of autotaxin(NPP2), a secreted metastasis-enhancing lysophospho lipase D. J Cell Sci118, 3081-3089 (2005), which is incorporated by reference in itsentirety). ATX is a member of the ectonucleotidepyrophosphatase/phosphodiesterase family of ectoenzymes (E-NPP) thathydrolyze phosphodiesterase (PDE) bonds of various nucleotides andderivatives (Stefan, C, Jansen, S. & Bollen, M. NPP-typeectophosphodiesterases: unity in diversity. Trends Biochem Sci 30,542-550 (2005), which is incorporated by reference in its entirety). Theenzymatic activity of ATX was enigmatic, until it was shown to beidentical to lysophospholipase D (lysoPLD) (Umezu-Goto, M., et al.Autotaxin has lysophospholipase D activity leading to tumor cell growthand motility by lysophosphatidic acid production. J Cell Biol 158,227-233 (2002), which is incorporated by reference in its entirety),which is widely present in biological fluids. Since ATX is aconstitutively active enzyme, the biological outcome of ATX action willlargely depend on its expression levels and the local availability ofits substrates. The major lysophospholipid substrate for ATX,lysophosphatidylcholine (LPC), is secreted by the liver and isabundantly present in plasma (at about 100 μM) as a predominantlyalbumin bound form (Croset, M., Brossard, N., Polette, A. & Lagarde, M.Characterization of plasma unsaturated lysophosphatidylcholines in humanand rat Biochem J 345 Pt 1, 61-67 (2000), which is incorporated byreference in its entirety). LPC is also detected in tumor-cellconditioned media (Umezu-Goto, M., et al.), presumably as a constituentof shed microvesicles. ATX, through its lysoPLD activity converts LPC tolysophosphatidic acid (LPA).

LPC is an important inflammatory mediator with recognized effects inmultiple cell types and pathophysiological processes. It is a majorcomponent of oxidized low density lipoprotein (oxLDL) and it can existin several other forms including free, micellar, bound to hydrophobicproteins such as albumin and incorporated in plasma membranes. It isproduced by the hydrolysis of phosphatidylcholine (PC) by PLA2 withconcurrent release of arachidonic acid and in turn of otherpro-inflammatory mediators (prostaglandins and leukotrienes). Moreover,LPC externalization constitutes a chemotactic signal to phagocyticcells, while interaction with its receptors can also stimulatelymphocytic responses. LPC has been shown to have therapeutic effects inexperimental sepsis, possibly by suppressing endotoxin-induced HMGB1release from macrophages/monocytes.

LPA, the product of ATX action on LPC, is a bioactive phospholipid withdiverse functions in almost every mammalian cell line (Moolenaar, W. H.,van Meeteren, L. A. & Giepmans, B. N. The ins and outs oflysophosphatidic acid signaling. Bioessays 28, 870-881 (2004), which isincorporated by reference in its entirety). LPA is a major constituentof serum bound tightly to albumin, gelsolin and possibly other as yetunidentified proteins. See, e.g., Goetzl, E. J., et al Gelsolin bindingand. cellular presentation of lysophosphatidic acid. J Biol Chem 275,14573-14578 (2000); and Tigyi, G. & Miledi, R, Lysophosphatidates boundto serum albumin activate membrane currents in Xenopus oocytes andneurite retraction in PC12 pheochromocytoma cells. J Biol Chem 267,21360-21367 (1992); each of which is incorporated by reference in itsentirety.

LPA is also found in other biofluids, such as saliva and follicularfluid, and has been implicated in a wide array of functions, such aswound heeling, tumor invasion and metastasis, neurogenesis, myelination,astrocytes outgrowth and neurite retraction. The long list of LPAfunctions was also explained with the discovery that it signals throughG-protein coupled receptors (GPCRs), via classical second messengerpathways. Five mammalian cell-surface LPA receptors have been identifiedso far. The best known are LPA1-3 (namely Edg-2, Edg-4 and Edg7) whichare all members of the so-called ‘endothelial differentiation gene’(EDG) family of GPCRs (Contos, J. J., Ishii, I. & Chun, J.Lysophosphatidic acid receptors. Mol Pharmacol 58, 1188-1196 (2000),which is incorporated by reference in its entirety). LPA receptors cancouple to at least three distinct G proteins (G_(q), G_(i) andG_(12/13)), which, in turn, feed into multiple effector systems. LPAactivates G_(q) and thereby stimulates phospholipase C (PLC), withsubsequent phosphatidylinositol-bisphosphate hydrolysis and generationof multiple second messengers leading to protein kinase C activation andchanges in cytosolic calcium. LPA also activates G_(i), which leads toat least three distinct signaling routes: inhibition of adenylyl cyclasewith inhibition of cyclic AMP accumulation; stimulation of the mitogenicRAS-MAPK (mitogen-activated protein kinase) cascade; and activation ofphosphatidylinositol 3-kinase (PI3K), leading to activation of theguanosine diphosphate/guanosine triphosphate (GDP/GTP) exchange factorTIAM1 and the downstream RAC GTPase, as well as to activation of theAKT/PKB antiapoptotic pathway. Finally, LPA activates G_(12/13), leadingto activation of the small GTPase RhoA, which drives cytoskeletalcontraction and cell rounding. So, LPA not only signals via classicsecond messengers such as calcium, diacylglycerol and cAMP, but it alsoactivates RAS- and RHO-family GTPases, the master switches that controlcell proliferation, migration and morphogenesis.

LPA signaling through the RhoA-Rho kinase pathway mediates neuriteretraction and inhibition of axon growth. Interfering with LPA signalinghas been shown to promote axonal regeneration and functional recoveryafter CNS injury or cerebral ischemia. (See Broggini, et al., MolecularBiology of the Cell (2010), 21:521-537.) It has been reported thataddition of LPA to dorsal root fibers in ex vivo culture causesdemyelination, whereas LPC fails to cause significant demyelination ofnerve fibers in ex vivo cultures without further addition of recombinantATX to the culture which when added caused significant demyelination atequivalent levels to LPA presumable due to conversion of LPC to LPAthrough the enzymatic activity of ATX. Moreover, injury induceddemyelination was attenuated by about 50% in atx^(+/−) mice (Nagai, etal., Molecular Pain (2010), 6:78).

A number of diseases or disorders involve demyelination of the centralor peripheral nervous system which can occur for a number of reasonssuch as immune dysfunction as in multiple sclerosis, encephalomyelitis,Guillain-Barre Syndrome, chronic inflammatory demyelinatingpolyneuropathy (CIDP), transverse myelitis, and optic neuritis;demyelination due to injury such as spinal cord injury, traumatic braininjury, stroke, acute ischemic optic neuropathy, or other ischemia,cerebral palsy, neuropathy (e.g. neuropathy due to diabetes, chronicrenal failure, hypothyroidism, liver failure, or compression of thenerve (e.g. in Bell's palsy)), post radiation injury, and centralpontine myelolysis (CPM); inherited conditions such asCharcot-Marie-Tooth disease (CMT), Sjogren-Larsson syndrome, Refsumdisease, Krabbe disease, Canavan disease, Alexander disease,Friedreich's ataxia, Pelizaeus-Merzbacher disease, Bassen-Kornzweigsyndrome, metachromatic leukodystrophy (MLD), adrenoleukodystrophy, andnerve damage due to pernicious anemia; viral infection such asprogressive multifocal leukoencephalopathy (PML), Lyme disease, or tabesdorsalis due to untreated syphilis; toxic exposure due to chronicalcoholism (which is a possible cause of Marchiafava-Bignami disease),chemotherapy, or exposure to chemicals such as organophosphates; ordietary deficiencies such as vitamin B12 deficiency, vitamin Edeficiency and copper deficiency. Other demyelination disorders may haveunknown causes or multiple causes such as trigeminal neuralgia,Marchiafava-Bignami disease and Bell's palsy. One particularlysuccessful approach to treating demyelination disorders which are causedby autoimmune dysfunction has been to attempt to limit the extent ofdemyelination by treating the patient with immunoregulatory drugs.However, typically this approach has merely postponed but not avoidedthe onset of disability in these patients. Patients with demyelinationdue to other causes have even fewer treatment options. Therefore, theneed exists to develop new treatments for patients with demyelinationdiseases or disorders.

SUMMARY

A compound of formula (I), or a pharmaceutically acceptable saltthereof, can be an S1P modulating agent and/or an ATX modulating agent,e.g., an S1P4 antagonist or ATX inhibitor.

In one aspect, a compound is represented by formula (I):

or a pharmaceutically acceptable salt thereof.

In formula (I), X can be O, S(O)_(r), NR¹², C(O) or CH₂, in which r is0, 1, or 2.

A¹, A², and A⁷ can each independently be CR² or N.

A³, A⁵, and A⁶ can each independently be CR², C(R²)₂, N, or NR¹⁹,wherein at least three of A¹, A², A³, A⁵, A⁶, and A⁷ are CR² or C(R²)₂.

“------” indicates a double or a single bond.

R¹ can be a C₆₋₂₀alkyl, a C₃₋₁₄carbocyclyl, a 3- to 15-memberedheterocyclyl, a C₆₋₁₀aryl, or a five- to 14-membered heteroaryl, whereinR¹ may be optionally substituted with from one to six independentlyselected R⁶.

R², for each occurrence, can be independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, cyano, carboxy,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈halocycloalkyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₃₋₈cycloalkoxy, C₃₋₈halocycloalkoxy,C₁₋₆alkanoyl, amino, N—(C₁₋₆alkyl)amino, N,N-di-(C₁₋₆alkyl)amino,C₁₋₆alkoxycarbonyl, C₁₋₆alkanoyloxy, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N-di-(C₁₋₆alkyl)carbamoyl, C₁₋₆alkylamido, mercapto, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, sulfamoyl, N—(C₁₋₆alkyl)sulfamoyl,N,N-di-(C₁₋₆alkyl)sulfamoyl, and C₁₋₆alkylsulfonamido.

each R³ and each R⁴ can each independently be hydrogen, a carboxy,C₁₋₆alkyl, or a C₂₋₆alkenyl; or R³ and R⁴ together with the carbon towhich they are attached are —C(═O)—, a C₃₋₈spirocycloalkyl, or a 3- to8-membered spiroheterocycloalkyl.

B can be a fused ring system, a bridged ring system, a spiro ringsystem, or a combination thereof; or B is a bicyclic ring systemrepresented by the following formula:

wherein B′ and B″ are each independently selected from the groupconsisting of monocyclic C₃₋₈carbocyclyl, a monocyclic 3- to 8-memberedheterocyclyl, phenyl, or a 5- to 6-membered heteroaryl, wherein theheterocyclyl and the heteroaryl comprises 1 to 3 heteroatomsindependently selected from N, S, or O; provided that when B is a fusedring system it is not 1H-benzo[d][1,2,3]triazole.

R⁵, for each occurrence, can be independently hydroxyl, halo, C₁₋₆alkyl,or —(CR¹⁷R¹⁸)_(p)—R⁷; or two R⁵ on the same carbon atom may be ═O.

R⁶, for each occurrence, can be independently selected from the groupconsisting of halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, C₆₋₁₀aryl, C₁₋₆alkoxy-C₁₋₆alkyl, andtri-(C₁₋₆alkyl)silyl; or two R⁶ that are attached to the same carbonatom may form C₃₋₈spirocycloalkyl or 3- to 8-memberedspiroheterocycloalkyl.

R⁷ can be —OH, —C(O)OR¹⁵, —C(O)N(R¹⁶)₂, —C(O)N(R¹⁵)—S(O)₂R¹⁵,—S(O)₂OR¹⁵—C(O)NHC(O)R⁵,

—Si(O)OH, —B(OH)₂, —N(R¹⁵)S(O)₂R¹⁵, —S(O)₂N(R¹⁵)₂, —O—P(O)(OR¹⁵)₂,—P(O)(OR¹⁵)₂, —CN, —S(O)₂NHC(O)R¹⁵, —C(O)NHS(O)₂R¹⁵, —C(O)NHOH,—C(O)NHCN, or a heteroaryl or a heterocyclyl selected from the groupconsisting of formulae (a)-(i′):

R⁸, R¹², and R¹⁹ can each independently be hydrogen or a C₁₋₆alkyl.

R¹⁵ for each occurrence can be independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₆₋₁₀aryl, a 5 to 14 memberedheteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroarylor heterocyclyl comprises from 1 to 10 heteroatoms independentlyselected from O, N, or S; and wherein R¹⁵ may be optionally substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of halo, C₁₋₄alkoxy, C₁₋₄alkyl, cyano, nitro, hydroxyl,amino, N—(C₁₋₄alkyl)amino, N,N-di-(C₁₋₄alkyl)amino, carbamoyl,N—(C₁₋₄alkyl)carbamoyl, N,N-di-(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylamido,C₁₋₄alkylsulfonyl, C₁₋₄alkylsulfonamido, sulfamoyl,N—(C₁₋₄alkyl)sulfamoyl, and N,N—(C₁₋₄dialkyl)-sulfamoyl.

R¹⁶ can be R¹⁵; or two R¹⁶ together with the nitrogen atom to which theyare attached can form a 5 to 14 membered heteroaryl or a 3 to 15membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprisesfrom 1 to 10 heteroatoms independently selected from O, N, or S; andwherein the heteroaryl or heterocyclyl may be optionally substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of halo, C₁₋₄alkoxy, C₁₋₄alkyl, cyano, nitro, hydroxyl,amino, N—(C₁₋₄alkyl)amino, N,N-di-(C₁₋₄alkyl)amino, carbamoyl,N—(C₁₋₄alkyl)carbamoyl, N,N-di-(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylamido,C₁₋₄alkylsulfonyl, C₁₋₄alkylsulfonamido, sulfamoyl,N—C₁₋₄alkylsulfamoyl, and N,N—(C₁₋₄dialkyl)-sulfamoyl.

R¹⁷ and R¹⁸, for each occurrence, can each independently be hydrogen, ahalo, or a C₁₋₄haloalkyl.

R^(c) is hydrogen or a C₁₋₄alkyl.

i can be an integer from 0 to 6.

n can be an integer from 1 to 6.

m can be 0 or 1, provided that when m is 0, B comprises at least onenitrogen.

p can be 0 or an integer from 1 to 6.

q can be 0, 1, 2, 3, or 4.

The compound is not2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)octahydrocyclopenta[c]pyrrole-3a-carboxylicacid or6-phenoxy-2-(2-(4-phenylpiperidin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-ol.

In some embodiments, q is 1 and R⁶ is t-butyl.

In some embodiments, q is 1 and R⁶ is methyl, ethyl or isopropyl.

In some embodiments, R⁶ is trifluoromethyl, difluoromethyl ormonofluoromethyl.

In some embodiments, B can be selected from the group consisting of9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl,decahydroisoquinolinyl, 2-azaspiro[3.3]heptanyl, bicyclo[3.2.1]octanyl,5-azaspiro[2.3]hexanyl, 3-cyclohexylazetidinyl, bicyclo[2.2.1]heptanyl,adamantyl, 6-oxa-9-azaspiro[4.5]decanyl, 3-azabicyclo[3.3.1]nonanyl,6-oxa-2-azaspiro[3.4]octanyl, 4-(1H-imidazol-4-yl)piperidinyl,octahydro-1H-pyrido[1,2-a]pyrazinyl, 2,3-dihydro-1H-indenyl,(1R,5S)-bicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl,1-(pyridin-4-yl)piperazinyl, 1-(pyridin-2-yl)piperazinyl,1-(pyridin-3-yl)piperazinyl, 2-oxa-6-azaspiro[3.3]heptanyl,4-(pyrimidin-2-yl)piperazin-1-yl, 3-azabicyclo[3.3.1]nonanyl,4-(pyridin-2-yl)piperidin-1-yl, 4-phenylpiperazin-1-yl,4-phenylpiperidin-1-yl, 4-(pyrazin-2-yl)piperazin-1-yl,4-(pyridin-2-yl)-1,4-diazepan-1-yl,4-(pyrimidin-2-yl)-1,4-diazepan-1-yl, 4-(pyrimidin-4-yl)piperazin-1-yl,2,7-diazaspiro[3.5]nonanyl, 3-phenylazetidinyl,2-oxa-7-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl,2,8-diazaspiro[4.5]decanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl,7-azabicyclo[2.2.1]heptanyl, spiro[3.5]nonanyl, andtricyclo[2.2.1.02,6]heptanyl.

In some embodiments, B can be a bridged ring system.

In some embodiments, m can be 1, B can be a ring system represented bythe following formula:

and R⁵ can be CO₂H.

In some embodiments, B can be a bridged ring system represented by thefollowing formula:

In some embodiments, m can be 0, B can be a ring system represented bythe following formula:

wherein B is optionally further substituted by oxo, hydroxy, —NH₂,—CONH₂, or —CO₂H; and R⁵ can be CO₂H.

In some embodiments, the compound can be represented by formula (II):

or a pharmaceutically acceptable salt thereof. In formula (II):

A^(1b), A^(2b), A^(3b), A^(5b), and A^(6b) can be CR^(2b) or N, whereinat least two of A^(1b), A^(2b), A^(3b), A^(5b), and A^(6b) are CR^(2b),

R^(2a) can be a halo, C₁₋₆haloalkyl or cyano, and

R^(2b), for each occurrence, can be independently selected from thegroup consisting of hydrogen, halo, hydroxyl, nitro, cyano, carboxy,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈halocycloalkyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₃₋₈cycloalkoxy, C₃₋₈halocycloalkoxy,C₁₋₆alkanoyl, amino, N—(C₁₋₆alkyl)amino, N,N-di-(C₁₋₆alkyl)amino,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C_(i-6)alkyl)carbamoyl,N,N-di-(C₁₋₆alkyl)carbamoyl, C₁₋₆alkylamido, mercapto, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, sulfamoyl, N—(C₁₋₆alkyl)sulfamoyl,N,N-di-(C₁₋₆alkyl)sulfamoyl, and C₁₋₆alkylsulfonamido.

In some embodiments, R^(2b), for each occurrence, can be independentlyhydrogen or a halo.

In some embodiments, compound can be represented by formula (IIa):

or a pharmaceutically acceptable salt thereof. In formula (IIa):

A^(3c) and A^(5c) can be N or CH, provided that only one of A^(3c) orA^(5c) is N,

R⁹ can be a halo, an C₁₋₆alkyl, or a C₁₋₆haloalkyl, and

R¹³ and R¹⁴ can each independently be hydrogen or a C₁₋₆alkyl.

In some embodiments, the compound can be represented by formula (IIb):

or a pharmaceutically acceptable salt thereof.

In some embodiments, m can be 0, B can be a ring system represented bythe following formula:

wherein B is optionally further substituted by oxo, hydroxy, —NH₂,—CONH₂, or —CO₂H; and R⁵ can be CO₂H.

In some embodiments, R^(2a) can be —Cl, —CF₃ or —CHF₂.

In some embodiments, R⁹ can be methyl, ethyl, —CF₃ or tert-butyl.

In some embodiments, the compound can be represented by formula (III):

or a pharmaceutically acceptable salt thereof. In formula (III):

A^(3c) can be N or CH, and R¹⁰ and R¹¹ can each independently behydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, tri-C₁₋₆alkylsilyl, or phenyl,wherein at least one of R¹⁰ or R¹¹ is not hydrogen; or R¹⁰ and R¹¹together with the carbon to which they are attached form aC₃₋₈spirocycloalkyl or 3- to 8-membered spiroheterocycloalkyl.

In some embodiments, m can be 1, B can be a bridged ring systemrepresented by the following formula:

and R⁵ can be CO₂H.

In some embodiments, X can be NH.

In some embodiments, the compound, or a pharmaceutically acceptable saltthereof, is selected from the group consisting of:

-   4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)    bicyclo[2.2.2]octane-1-carboxylic acid;-   4-(((6-((trans-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-pentyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[2.5]octan-6-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[3.5]nonan-7-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-methylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-pentyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-phenylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[2.5]octan-6-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[3.5]nonan-7-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[4.5]decan-8-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[5.5]undecan-3-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate;-   4-(((6-((cis-4-methylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-phenylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)meth    yl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;-   2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine;-   2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyrimidine;    1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-phenylpiperazine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-3-yl)piperazine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)-1,4-diazepane;-   2-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrimidine;-   2-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrazine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-4-yl)piperazine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyrimidin-2-yl)-1,4-diazepane;-   4-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrimidine;-   4-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)-2-methylpyrimidine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-phenylpiperidine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine;-   1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine;-   1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine;-   1-(pyridin-2-yl)-4-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)piperazine;-   1-((6-(heptyloxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine;-   6-((cis-4-isopropylcyclohexyl)oxy)-2-((4-(pyridin-2-yl)piperazin-1-yl)methyl)quinoline;-   3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(heptyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohex    anecarboxylic acid;-   3-(1-((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohex    anecarboxylic acid;-   3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   4-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   6-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-oxa-6-azaspiro    [3.3]heptane;-   3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)(methyl)amino    )bicyclo[2.2.2]octane-1-carboxylic acid;-   8-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylic    acid;-   3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo    [3.1.1]heptane-6-carboxylic acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo    [2.2.1]heptane-1-carboxylic acid;-   4-((6-(trans-4-(Trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methylamino)bicyclo    [2.2.2]octane-1-carboxylic acid;-   4-(((6-((cis-4-(Trimethylsilyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo    [2.2.2]octane-1-carboxylic acid;-   4-((6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylic    acid;-   4-((6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl)methylamino)-1-(hydroxymethyl)bicyclo[2.2.2]octan-2-ol;    and-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound can be selected from the groupconsisting of:

-   9-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   3-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)amino)spiro[3.5]nonane-1-carboxylic    acid;-   3-(4-{[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]oct-1-yl)-propionic    acid;-   3-(4-(methyl((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)amino)bicyclo[2.2.2]octan-1-yl)propanoic    acid;-   9-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]-nonane-3-carboxylic    acid;-   9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid, enantiomer 1;-   9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid, enantiomer 2;-   8-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-(trifluoromethyl)    naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((cis-4-methylcyclohexyl)amino)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   2-(9-Azabicyclo[3.3.1]nonan-9-yl)-2-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)acetic    acid;-   9-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-Chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   4-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylic    acid;-   N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-1-aminoindane-6-carboxylic    acid;-   N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-6-aminoindole-3-carboxylic    acid;-   N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-2-azabicyclo[1.2.3]octane-7-carboxylic    acid;-   N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-decahydroisoquinoline-5-carboxylic    acid;-   2-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-2-azabicyclo[1.2.3]octane-7-carboxylic    acid;-   2-(2-(5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-2-azabicyclo[1.2.3]octane-7-carboxylic    acid;-   4-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)aminomethyl)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylic    acid;-   7-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-tricyclo[3.1.1.0]heptane-5-carboxylic    acid;-   8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalene-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   3-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-7,7-dimethylbicyclo[2.2.1]heptane-4-carboxylic    acid;-   8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-aza-7-oxa-bicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-7-hydroxy-9-aza-bicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 2;-   9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid, enantiomer 1;-   9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid, enantiomer 2;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 2;-   9-((6-((cis-4-trifluoromethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   methyl    2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-(7R,9aR)-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic    acid;-   3-(4-{[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]oct-1-yl)-carboxylic    acid;-   2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-(7R,9aR)-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic    acid;-   2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylic    acid;-   N-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-amino-indane-5-carboxylic    acid;-   3-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic    acid;-   2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-azaspiro[3.2]hexane-5-carboxylic    acid;-   N-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-decahydroisoquinoline-8-carboxylic    acid;-   3-((6-((cis-4-trifluoromethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylic    acid;-   N-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-4-aminobicyclo[2.2.1]heptane-1-carboxylic    acid;-   N-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-1-aminoadamantane-3-carboxylic    acid;-   3-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-3-azabicyclo[3.3.0]octane-7-carboxylic    acid;-   2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-((9S,9aR)-octahydro-1H-pyrido[1,2-a]pyrazin-9-yl)methanol;-   8-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   2-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-2-aza-6-oxaspiro[3.4]octane-7-carboxylic    acid;-   (1R,5S,7r)-3-((2-(4-(trifluoromethyl)cyclohexyloxy)-1-(trifluoromethyl)naphthalen-6-yl)methyl)-3-aza-bicyclo[3.3.1]nonane-7-carboxylic    acid;-   N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-3-(azetidine-3-yl)-cyclohexane-1-carboxylic    acid;-   8-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   2-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-2-aza-5-oxaspiro[5.4]decane-8-carboxylic    acid;-   N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-8-aminobicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-8-aminobicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 2;-   N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-1-amino-3,5-dimethyladamantane;-   7-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic    acid;-   N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-aminobicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-aza-7-oxabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-azabicyclo[3.3.1]nonane;-   9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-hydroxy-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-oxo-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 2;-   9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)    propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;-   8-(1-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)    propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-chloronaphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-Chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid; and-   8-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;

or a pharmaceutically acceptable salt thereof.

In another aspect, a pharmaceutical composition can include apharmaceutically acceptable carrier or excipient and a compound, or apharmaceutically acceptable salt thereof, according to any one offormulae (I), (IIa), (IIb) or (III).

In another aspect, a method of preventing, treating, or reducingsymptoms of a condition mediated by S1P activity or ATX activity in amammal can include administering to said mammal an effective amount of acompound according to any one of formulae (I), (IIa), (IIb) or (III), ora pharmaceutically acceptable salt thereof.

In some embodiments, the condition can be selected from the groupconsisting of multiple sclerosis, an autoimmune disease, a chronicinflammatory disorder, asthma, an inflammatory neuropathy, arthritis,transplantation rejection, Crohn's disease, ulcerative colitis, lupuserythematosis, psoriasis, an ischemia-reperfusion injury, a solid tumor,a tumor metastasis, a disease associated with angiogenesis, a vasculardisease, a pain condition, an acute viral disease, an inflammatory bowelcondition, insulin-dependent diabetes, non-insulin dependent diabetes, afibrosis of the lung, or a malignancy of the lung in a mammal.

In some embodiments, the condition can be multiple sclerosis.

In some embodiments, the condition can be rheumatoid arthritis.

In some embodiments, the method can include administering to the mammalan effective amount of one or more drugs selected from the groupconsisting of: a corticosteroid, a bronchodilator, an antiasthmatic, anantiinflammatory, an antirheumatic, an immunosuppressant, anantimetabolite, an immunomodulating agent, an antipsoriatic, and anantidiabetic.

In another aspect, a method of preventing, treating, or reducing chronicpain in a mammal can include comprising administering to said mammal aneffective amount of a compound according to any one of any one offormulae (I), (IIa), (IIb) or (III), or a pharmaceutically acceptablesalt thereof.

In some embodiments, the chronic pain can be inflammatory pain.

In some embodiments, the chronic pain can be neuropathic pain.

Other features or advantages will be apparent from the followingdetailed description of several embodiments, and also from the appendedclaims.

DETAILED DESCRIPTION

The disclosed compounds can be S1P modulating agents and/or ATXmodulating agents. In other words, the disclosed compounds can haveactivity as receptor agonists or receptor antagonists at one or more S1Preceptors, or as an ATX modulating agent. In particular, the compoundscan be S1P4 antagonists, or ATX inhibitors. A given compound can be anS1P modulating agent with little or substantially no ATX activity; orcan be an ATX modulating agent with little or substantially no S1Pactivity; or, in some cases, can simultaneously be an S1P modulatingagent and an ATX modulating agent. Preferably, a given compound iseither an S1P modulating agent with little or substantially no ATXactivity; or is an ATX modulating agent with little or substantially noS1P activity.

A compound, or a pharmaceutically acceptable salt thereof, can berepresented by formula (I):

In formula (I), X can be O, S(O)_(r), NR¹², C(O) or CH₂, wherein r is 0,1, or 2; A¹, A², and A⁷ can each independently be CR² or N; A³, A⁵, andA⁶ can each independently be CR², C(R²)₂, N, or NR¹⁹, wherein at leastthree of A¹, A², A³, A⁵, A⁶, and A⁷ are CR² or C(R²)₂.

“------” can indicate a double or a single bond.

R¹ can be a C₆₋₂₀alkyl, a C₃₋₁₄carbocyclyl, a 3- to 15-memberedheterocyclyl, a C₆₋₁₀aryl, or a five- to 14-membered heteroaryl, whereinR¹ may be optionally substituted with from one to six independentlyselected R⁶.

R², for each occurrence, can be independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, cyano, carboxy,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈halocycloalkyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₃₋₈cycloalkoxy, C₃₋₈halocycloalkoxy,C₁₋₆alkanoyl, amino, N—(C₁₋₆alkyl)amino, N,N-di-(C₁₋₆alkyl)amino,C₁₋₆alkoxycarbonyl, C₁₋₆alkanoyloxy, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N-di-(C₁₋₆alkyl)carbamoyl, C₁₋₆alkylamido, mercapto, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, sulfamoyl, N—(C₁₋₆alkyl)sulfamoyl,N,N-di-(C₁₋₆alkyl)sulfamoyl, and C₁₋₆alkylsulfonamido.

Each R³ and each R⁴ can each independently be hydrogen, a carboxy,C₁₋₆alkyl, or a C₂₋₆alkenyl; or R³ and R⁴ together with the carbon towhich they are attached can be —C(═O)—, a C₃₋₈spirocycloalkyl, or a 3-to 8-membered spiroheterocycloalkyl.

B can be a fused ring system, a bridged ring system, a spiro ringsystem, or a combination thereof; or B can be a bicyclic ring systemrepresented by the following formula:

wherein B′ and B″ can each independently be selected from the groupconsisting of monocyclic C₃₋₈carbocyclyl, a monocyclic 3- to 8-memberedheterocyclyl, phenyl, or a 5- to 6-membered heteroaryl, wherein theheterocyclyl and the heteroaryl comprises 1 to 3 heteroatomsindependently selected from N, S, or O; provided that when B is a fusedring system it is not 1H-benzo[d][1,2,3]triazole.

R⁵, for each occurrence, can independently be hydroxyl, halo, C₁₋₆alkyl,or —(CR¹⁷R¹⁸)_(p)—R⁷; or two R⁵ on the same carbon atom may be ═O.

R⁶, for each occurrence, can be independently selected from the groupconsisting of halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, C₆₋₁₀aryl, C₁₋₆alkoxy-C₁₋₆alkyl, andtri-(C₁₋₆alkyl)silyl; or two R⁶ that are attached to the same carbonatom may form C₃₋₈spirocycloalkyl or 3- to 8-memberedspiroheterocycloalkyl.

R⁷ can be —OH, —C(O)OR¹⁵, —C(O)N(R¹⁶)₂, —C(O)N(R¹⁵)—S(O)₂R¹⁵,—S(O)₂OR¹⁵, —C(O)NHC(O)R¹⁵,

—Si(O)OH, —B(OH)₂, —N(R¹⁵)S(O)₂R¹⁵, —S(O)₂N(R¹⁵)₂, —O—P(O)(OR¹⁵)₂,—P(O)(OR¹⁵)₂, —CN, —S(O)₂NHC(O)R¹⁵, —C(O)NHS(O)₂R¹⁵, —C(O)NHOH,—C(O)NHCN, —N(R²⁰)₂, or a heteroaryl or a heterocyclyl selected from thegroup consisting of formulae (a)-(i′):

R⁸, R¹², R¹⁹, and R²⁰ can each independently be hydrogen or a C₁₋₆alkyl.

R¹⁵ for each occurrence can be independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₆₋₁₀aryl, a 5 to 14 memberedheteroaryl, and a 3 to 15 membered heterocyclyl; wherein the heteroarylor heterocyclyl can comprise from 1 to 10 heteroatoms independentlyselected from O, N, or S; and wherein R¹⁵ may be optionally substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of halo, C₁₋₄alkoxy, C₁₋₄alkyl, cyano, nitro, hydroxyl,amino, N—(C₁₋₄alkyl)amino, N,N-di-(C₁₋₄alkyl)amino, carbamoyl,N—(C₁₋₄alkyl)carbamoyl, N,N-di-(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylamido,C₁₋₄alkylsulfonyl, C₁₋₄alkylsulfonamido, sulfamoyl,N—(C₁₋₄alkyl)sulfamoyl, and N,N—(C₁₋₄dialkyl)-sulfamoyl.

R¹⁶ can be R¹⁵; or two R¹⁶ together with the nitrogen atom to which theyare attached can form a 5 to 14 membered heteroaryl or a 3 to 15membered heterocyclyl, wherein the heteroaryl or heterocyclyl cancomprise from 1 to 10 heteroatoms independently selected from O, N, orS; and wherein the heteroaryl or heterocyclyl may be optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of halo, C₁₋₄alkoxy, C₁₋₄alkyl, cyano, nitro,hydroxyl, amino, N—(C₁₋₄alkyl)amino, N,N-di-(C₁₋₄alkyl)amino, carbamoyl,N—(C₁₋₄alkyl)carbamoyl, N,N-di-(C₁₋₄alkyl)carbamoyl, C₁₋₄alkylamido,C₁₋₄alkylsulfonyl, C₁₋₄alkylsulfonamido, sulfamoyl,N—C₁₋₄alkylsulfamoyl, and N,N—(C₁₋₄dialkyl)-sulfamoyl.

R¹⁷ and R¹⁸, for each occurrence, can each independently be hydrogen, ahalo, or a C₁₋₄haloalkyl.

R^(c) is hydrogen or a C₁₋₄alkyl.

i can be an integer from 0 to 6.

n can be 0 or an integer from 1 to 6, provided that when n is 0, then mis 1, q is 0 and R¹ is a C₃₋₁₄carbocyclyl which is optionallysubstituted with from one to six R⁶.

m can be 0 or 1, provided that when m is 0, B comprises at least onenitrogen.

p can be 0 or an integer from 1 to 6.

q can be 0, 1, 2, 3, or 4.

The compound of formula is not2-((6-(trans-4-tert-butylcyclohexyloxy)-naphthalen-2-yl)methyl)octahydrocyclopenta[c]pyrrole-3a-carboxylicacid or6-phenoxy-2-(2-(4-phenylpiperidin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-ol.

In some embodiments, B can be selected from the group consisting of9-azabicyclo[3.3.1]nonanyl, 8-azabicyclo[3.2.1]octanyl,decahydroisoquinolinyl, 2-azaspiro[3.3]heptanyl, bicyclo[3.2.1]octanyl,5-azaspiro[2.3]hexanyl, 3-cyclohexylazetidinyl, bicyclo[2.2.1]heptanyl,adamantyl, 6-oxa-9-azaspiro[4.5]decanyl, 3-azabicyclo[3.3.1]nonanyl,6-oxa-2-azaspiro[3.4]octanyl, 4-(1H-imidazol-4-yl)piperidinyl,octahydro-1H-pyrido[1,2-a]pyrazinyl, 2,3-dihydro-1H-indenyl,(1R,5S)-bicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl,1-(pyridin-4-yl)piperazinyl, 1-(pyridin-2-yl)piperazinyl,1-(pyridin-3-yl)piperazinyl, 2-oxa-6-azaspiro[3.3]heptanyl,4-(pyrimidin-2-yl)piperazin-1-yl, 3-azabicyclo[3.3.1]nonanyl,4-(pyridin-2-yl)piperidin-1-yl, 4-phenylpiperazin-1-yl,4-phenylpiperidin-1-yl, 4-(pyrazin-2-yl)piperazin-1-yl,4-(pyridin-2-yl)-1,4-diazepan-1-yl,4-(pyrimidin-2-yl)-1,4-diazepan-1-yl, 4-(pyrimidin-4-yl)piperazin-1-yl,2,7-diazaspiro[3.5]nonanyl, 3-phenylazetidinyl,2-oxa-7-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl,2,8-diazaspiro[4.5]decanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl,7-azabicyclo[2.2.1]heptanyl, spiro[3.5]nonanyl, andtricyclo[2.2.1.02,6]heptanyl.

B can be a bridged ring system.

In some embodiments, m can be 1; B can be a ring system represented bythe following formula:

and R⁵ can be CO₂H.

B can be a bridged ring system represented by the following formula:

In some embodiments, m can be 0; B can be a ring system represented bythe following formula:

wherein B is optionally further substituted by oxo, hydroxy, —NH₂,—CONH₂, or —CO₂H; and R⁵ can be CO₂H.

B can be a bridged ring system selected from 9-aza-bicyclo[3.3.1]nonanesubstituted with R⁵ at the 3-position; and 8-aza-bicyclo[3.2.1]octanesubstituted with R⁵ at the 3-position.

In some embodiments, the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, can be represented by formula (II):

In formula (II), A^(1b), A^(2b), A^(3b), A^(5b), and A^(6b) can beCR^(2b) or N, wherein at least two of A^(1b), A^(2b), A^(3b), A^(5b),and A^(6b) can be CR^(2b).

R^(2a) can be a halo, C₁₋₆haloalkyl or cyano.

R^(2b), for each occurrence, can be independently selected from thegroup consisting of hydrogen, halo, hydroxyl, nitro, cyano, carboxy,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈halocycloalkyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₃₋₈cycloalkoxy, C₃₋₈halocycloalkoxy,C₁₋₆alkanoyl, amino, N—(C₁₋₆alkyl)amino, N,N-di-(C₁₋₆alkyl)amino,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N-di-(C₁₋₆alkyl)carbamoyl, C₁₋₆alkylamido, mercapto, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, sulfamoyl, N—(C₁₋₆alkyl)sulfamoyl,N,N-di-(C₁₋₆alkyl)sulfamoyl, and C₁₋₆alkylsulfonamido.

In some embodiments of formula (II), R^(2b), for each occurrence, canindependently be hydrogen or a halo.

In some embodiments, the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, can be represented by formula (IIa):

In formula (IIa), A^(3c) and A^(5c) can be N or CH, provided that onlyone of A^(3c) or A^(5c) is N.

R⁹ can be a halo, an C₁₋₆alkyl, or a C₁₋₆haloalkyl.

R¹³ and R¹⁴ can each independently be hydrogen or a C₁₋₆alkyl.

In some embodiments, the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, can be represented by formula (IIb):

In some embodiments, for a compound of formula (II), (IIa), or (IIb), ora pharmaceutically acceptable salt thereof, m can be 0; B can be a ringsystem represented by the following formula:

wherein B is optionally further substituted by oxo, hydroxy, —NH₂,—CONH₂, or —CO₂H; and R⁵ can be CO₂H.

In some embodiments, for a compound of formula (II), (IIa), or (IIb), ora pharmaceutically acceptable salt thereof, B can be a bridged ringsystem selected from 9-aza-bicyclo[3.3.1]nonane substituted with R⁵ atthe 3-position; and 8-aza-bicyclo[3.2.1]octane substituted with R⁵ atthe 3-position.

In some embodiments, for a compound of formula (II), (IIa), or (IIb), ora pharmaceutically acceptable salt thereof, R^(2a) can be —Cl, —CF₃ or—CHF₂.

In some embodiments, for a compound of formula (IIb), or apharmaceutically acceptable salt thereof, R⁹ can be methyl, ethyl, —CF₃or tert-butyl.

In some embodiments, the compound of formula (I), or a pharmaceuticallyacceptable salt thereof, can be represented by formula (III):

In formula (III), A^(3c) can be N or CH.

R¹⁰ and R¹¹ can each independently be hydrogen, C₁₋₆alkyl,C₁₋₆haloalkyl, tri-C₁₋₆alkylsilyl, or phenyl, wherein at least one ofR¹⁰ or R¹¹ is not hydrogen; or R¹⁰ and R¹¹ together with the carbon towhich they are attached can form a C₃₋₈spirocycloalkyl or 3- to8-membered spiroheterocycloalkyl.

In some embodiments, for a compound of formula (III), or apharmaceutically acceptable salt thereof, m can be 1; B can be a bridgedring system represented by the following formula:

and R⁵ can be CO₂H.

A compound can be selected from the group consisting of:

-   4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)    bicyclo[2.2.2]octane-1-carboxylic acid;-   4-(((6-((trans-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-pentyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[2.5]octan-6-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[3.5]nonan-7-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-methylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-pentyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-phenylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[2.5]octan-6-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[3.5]nonan-7-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[4.5]decan-8-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[5.5]undecan-3-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate;-   4-(((6-((cis-4-methylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-phenylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine;-   2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyrimidine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-phenylpiperazine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-3-yl)piperazine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)-1,4-diazepane;-   2-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrimidine;-   2-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrazine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-4-yl)piperazine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyrimidin-2-yl)-1,4-diazepane;-   4-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrimidine;-   4-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)-2-methylpyrimidine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-phenylpiperi    dine;-   1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine;-   1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine;-   1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine;-   1-(pyridin-2-yl)-4-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)piperazine;-   1-((6-(heptyloxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine;-   6-((cis-4-isopropylcyclohexyl)oxy)-2-((4-(pyridin-2-yl)piperazin-1-yl)methyl)quinoline;-   3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(heptyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   4-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   6-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane;-   3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)(methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   8-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylic    acid;-   3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic    acid;-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic    acid;-   4-((6-(trans-4-(Trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-((cis-4-(Trimethylsilyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-((6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-hydroxy    bicyclo[2.2.2]octane-1-carboxylic acid;-   4-((6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl)methylamino)-1-(hydroxy    methyl)bicyclo[2.2.2]octan-2-ol; and-   4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;

or a pharmaceutically acceptable salt thereof.

A compound can be selected from the group consisting of:

-   9-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   3-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)amino)spiro[3.5]nonane-1-carboxylic    acid;-   3-(4-{[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]oct-1-yl)-propionic    acid;-   3-(4-(methyl((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)amino)bicyclo[2.2.2]octan-1-yl)propanoic    acid;-   9-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]-nonane-3-carboxylic    acid;-   9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid, enantiomer 1;-   9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid, enantiomer 2;-   8-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-(trifluoromethyl)    naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((cis-4-methylcyclohexyl)amino)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   2-(9-Azabicyclo[3.3.1]nonan-9-yl)-2-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)acetic    acid;-   9-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-Chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   4-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylic    acid;-   N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-1-aminoindane-6-carboxylic    acid;-   N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-6-aminoindole-3-carboxylic    acid;-   N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-2-azabicyclo[1.2.3]octane-7-carboxylic    acid;-   N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-decahydroisoquinoline-5-carboxylic    acid;-   2-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-2-azabicyclo[1.2.3]octane-7-carboxylic    acid;-   2-(2-(5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-2-azabicyclo[1.2.3]octane-7-carboxylic    acid;-   4-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)aminomethyl)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylic    acid;-   7-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-tricyclo[3.1.1.0]heptane-5-carboxylic    acid;-   8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalene-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   3-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-7,7-dimethylbicyclo[2.2.1]heptane-4-carboxylic    acid;-   8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-aza-7-oxa-bicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-7-hydroxy-9-aza-bicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 2;-   9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid, enantiomer 1;-   9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid, enantiomer 2;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 2;-   9-((6-((cis-4-trifluoromethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   methyl    2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-(7R,9aR)-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic    acid;-   3-(4-{[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl    ]-amino}-bicyclo[2.2.2]oct-1-yl)-carboxylic acid;-   2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-(7R,9aR)-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic    acid;-   2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylic    acid;-   N-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-amino-indane-5-carboxylic    acid;-   3-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic    acid;-   2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-azaspiro[3.2]hexane-5-carboxylic    acid;-   N-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-decahydroisoquinoline-8-carboxylic    acid;-   3-((6-((cis-4-trifluoromethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylic    acid;-   N-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-4-aminobicyclo[2.2.1]heptane-1-carboxylic    acid;-   N-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-1-aminoadamantane-3-carboxylic    acid;-   3-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-3-azabicyclo[3.3.0]octane-7-carboxylic    acid;-   2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-((9S,9aR)-octahydro-1H-pyrido[1,2-a]pyrazin-9-yl)methanol;-   8-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   2-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-2-aza-6-oxaspiro[3.4]octane-7-carboxylic    acid;-   (1R,5S,7r)-3-((2-(4-(trifluoromethyl)cyclohexyloxy)-1-(trifluoromethyl)naphthalen-6-yl)methyl)-3-aza-bicyclo[3.3.1]nonane-7-carboxylic    acid;-   N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-3-(azetidine-3-yl)-cyclohexane-1-carboxylic    acid;-   8-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   2-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-2-aza-5-oxaspiro[5.4]decane-8-carboxylic    acid;-   N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-8-aminobicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-8-aminobicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 2;-   N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-1-amino-3,5-dimethyladamantane;-   7-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic    acid;-   N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-aminobicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-aza-7-oxabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-azabicyclo[3.3.1]nonane;-   9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-hydroxy-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-oxo-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 1;-   8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid, enantiomer 2;-   9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)    propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;-   8-(1-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)    propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-chloronaphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-Chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid; and-   8-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo-   [3.2.1]octane-3-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

The term “fused ring system,” as used herein, is a ring system that hastwo or three rings (preferably two rings) independently selected fromcarbocyclyl, heterocyclyl, aryl or heteroaryl rings that share one side.A fused ring system may have from 4-15 ring members, preferably from5-10 ring members. Examples of fused ring systems includeoctahydroisoquinolin-2(1H)-yl, 2,3-dihydro-1H-indenyl,octahydro-1H-pyrido[1,2-a]pyrazinyl, and decahydroisoquinolinyl).

The term “bridged ring system,” as used herein, is a ring system thathas a carbocyclyl or heterocyclyl ring wherein two non-adjacent atoms ofthe ring are connected (bridged) by one or more (preferably from one tothree) atoms selected from C, N, O, or S. A bridged ring system can havemore than one bridge within the ring system (e.g., adamantyl). A bridgedring system may have from 6-10 ring members, preferably from 7-10 ringmembers. Examples of bridged ring systems include adamantyl,9-azabicyclo[3.3.1]nonan-9-yl, 8-azabicyclo[3.2.1]octanyl,bicyclo[2.2.2]octanyl, 3-azabicyclo[3.1.1]heptanyl,bicyclo[2.2.1]heptanyl, (1R,5S)-bicyclo[3.2.1]octanyl,3-azabicyclo[3.3.1]nonanyl, and bicyclo[2.2.1]heptanyl. More preferably,the bridged ring system is selected from the group consisting of9-azabicyclo[3.3.1]nonan-9-yl, 8-azabicyclo[3.2.1]octanyl, andbicyclo[2.2.2]octanyl.

The term “spiro ring system,” as used herein, is a ring system that hastwo rings each of which are independently selected from a carbocyclyl ora heterocyclyl, wherein the two ring structures having one atom incommon. Spiro ring systems have from 5 to 14 ring members. Example ofspiro ring systems include 2-azaspiro[3.3]heptanyl, spiropentanyl,2-oxa-6-azaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl,2-oxa-7-azaspiro[3.5]nonanyl, 6-oxa-9-azaspiro[4.5]decanyl,6-oxa-2-azaspiro[3.4]octanyl, 5-azaspiro[2.3]hexanyl and2,8-diazaspiro[4.5]decanyl.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 20carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbonatoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In some embodiments,an alkyl comprises from 6 to 20 carbon atoms. Representative examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.

“Alkylene” refers to a divalent alkyl group. Examples of alkylene groupsinclude methylene, ethylene, propylene, n-butylene, and the like. Thealkylene is attached to the rest of the molecule through a single bondand to the radical group through a single bond. The points of attachmentof the alkylene to the rest of the molecule and to the radical group canbe through one carbon or any two carbons within the carbon chain.

As used herein, the term “haloalkyl” refers to an alkyl, as definedherein, that is substituted by one or more halo groups as definedherein. Preferably the haloalkyl can be monohaloalkyl, dihaloalkyl orpolyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo,bromo, chloro or fluoro substituent. Dihaloalkyl and polyhaloalkylgroups can be substituted with two or more of the same halo atoms or acombination of different halo groups. Non-limiting examples of haloalkylinclude fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refersto an alkyl having all hydrogen atoms replaced with halo atoms.Preferred haloalkyl groups are trifluoromethyl and difluoromethyl.

“Halogen” or “halo” may be fluoro, chloro, bromo or iodo.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Preferably, alkoxy groups have about 1-6 carbon atoms, morepreferably about 1-4 carbon atoms.

As used herein, the term “haloalkoxy” refers to haloalkyl-O—, whereinhaloalkyl is defined herein above. Representative example of haloalkoxygroups are trifluoromethoxy, difluoromethoxy, and 1,2-dichloroethoxy.Preferably, haloalkoxy groups have about 1-6 carbon atoms, morepreferably about 1-4 carbon atoms.

As used herein, the term “alkylthio” refers to alkyl-S—, wherein alkylis defined herein above.

As used herein, the term “carbocyclyl” refers to saturated or partiallyunsaturated (but not aromatic) monocyclic, bicyclic or tricyclichydrocarbon groups of 3-14 carbon atoms, preferably 3-9, or morepreferably 3-8 carbon atoms. Carbocyclyls include fused or bridged ringsystems. The term “carbocyclyl” encompasses cycloalkyl groups. The term“cycloalkyl” refers to completely saturated monocyclic, bicyclic ortricyclic hydrocarbon groups of 3-12 carbon atoms, preferably 3-9, ormore preferably 3-8 carbon atoms. Exemplary monocyclic carbocyclylgroups include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl. Exemplarybicyclic carbocyclyl groups include bornyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,or bicyclo[2.2.2]octyl. Exemplary tricyclic carbocyclyl groups includeadamantyl.

As used herein, the term “halocycloalkyl” refers to a cycloalkyl, asdefined herein, that is substituted by one or more halo groups asdefined herein. Preferably the halocycloalkyl can be monohalocycloalkyl,dihalocycloalkyl or polyhalocycloalkyl including perhalocycloalkyl. Amonohalocycloalkyl can have one iodo, bromo, chloro or fluorosubstituent. Dihalocycloalkyl and polyhalocycloalkyl groups can besubstituted with two or more of the same halo atoms or a combination ofdifferent halo groups.

As used herein, the term “cycloalkoxy” refers to cycloalkyl-O—, whereincycloalkyl is defined herein above.

As used herein, the term “halocycloalkoxy” refers to halocycloalkyl-O—,wherein halocycloalkyl is defined herein above.

The term “spirocycloalkyl” as used herein, is a cycloalkyl that has onering atom in common with the group to which it is attached.Spirocycloalkyl groups may have from 3 to 14 ring members. In apreferred embodiment, the spirocycloalkyl has from 3 to 8 ring carbonatoms and is monocyclic.

The term “aryl” refers to monocyclic, bicyclic or tricyclic aromatichydrocarbon groups having from 6 to 14 carbon atoms in the ring portion.In one embodiment, the term aryl refers to monocyclic and bicyclicaromatic hydrocarbon groups having from 6 to 10 carbon atoms.Representative examples of aryl groups include phenyl, naphthyl,fluorenyl, and anthracenyl.

The term “aryl” also refers to a bicyclic or tricyclic group in which atleast one ring is aromatic and is fused to one or two non-aromatichydrocarbon ring(s). Nonlimiting examples include tetrahydronaphthalene,dihydronaphthalenyl and indanyl.

As used herein, the term “heterocyclyl” refers to a saturated orunsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring systemwhich has from 3- to 15-ring members at least one of which is aheteroatom, and up to 10 of which may be heteroatoms, wherein theheteroatoms are independently selected from O, S and N, and wherein Nand S can be optionally oxidized to various oxidation states. In oneembodiment, a heterocyclyl is a 3-8-membered monocyclic. In anotherembodiment, a heterocyclyl is a 6-12-membered bicyclic. In yet anotherembodiment, a heterocyclycyl is a 10-15-membered tricyclic ring system.The heterocyclyl group can be attached at a heteroatom or a carbon atom.Heterocyclyls include fused or bridged ring systems. The term“heterocyclyl” encompasses heterocycloalkyl groups. The term“heterocycloalkyl” refers to completely saturated monocyclic, bicyclicor tricyclic heterocyclyl comprising 3-15 ring members, at least one ofwhich is a heteroatom, and up to 10 of which may be heteroatoms, whereinthe heteroatoms are independently selected from O, S and N, and whereinN and S can be optionally oxidized to various oxidation states. Examplesof heterocyclyls include dihydrofuranyl, [1,3]dioxolane, 1,4-dioxane,1,4-dithiane, piperazinyl, 1,3-dioxolane, imidazolidinyl, imidazolinyl,pyrrolidine, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane,1,3-dithianyl, oxathianyl, thiomorpholinyl, oxiranyl, aziridinyl,oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepinyl,oxapinyl, oxazepinyl and diazepinyl.

The term “spiroheterocycloalkyl” as used herein, is a heterocycloalkylthat has one ring atom in common with the group to which it is attached.Spiroheterocycloalkyl groups may have from 3 to 15 ring members. In apreferred embodiment, the spiroheterocycloalkyl has from 3 to 8 ringatoms selected from carbon, nitrogen, sulfur and oxygen and ismonocyclic.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic-, bicyclic-, or tricyclic-ring system, having 1 to 10heteroatoms independently selected from N, O or S, wherein N and S canbe optionally oxidized to various oxidation states, and wherein at leastone ring in the ring system is aromatic. In one embodiment, theheteroaryl is monocyclic and has 5 or 6 ring members. Examples ofmonocyclic heteroaryl groups include pyridyl, thienyl, furanyl,pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl. Inanother embodiment, the heteroaryl is bicyclic and has from 8 to 10 ringmembers. Examples of bicyclic heteroaryl groups include indolyl,benzofuranyl, quinolyl, isoquinolyl indazolyl, indolinyl, isoindolyl,indolizinyl, benzamidazolyl, quinolinyl, 5,6,7,8-tetrahydroquinoline and6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine.

An amino is a group having the formula NH₂—. The term N-alkylamino is anamino group in which one of the hydrogen atoms is replaced with an alkylgroup. The term N,N-dialkylamino is an amino group in which eachhydrogen atoms is replaced with an alkyl group which may be the same ordifferent.

The term “alkanoyl” refers to alkyl-C(O)— wherein the alkyl is definedas above.

The term “alkoxycarbonyl” refers to alkoxy-C(O)—, wherein the alkoxygroup is defined as above.

The term “alkanoyloxy” refers to alkyl-C(O)O—, wherein the alkyl isdefined as above.

A carbamoyl is a group having the formula NH₂C(O)—. The termN-alkylcarbamoyl is a carbamoyl group in which one of the hydrogen atomsis replaced with an alkyl group. The term N,N-dialkylcarbamoyl is acarbamoyl group in which each hydrogen atoms is replaced with an alkylgroup which may be the same or different.

The term “alkylamido” refers to a group having the formulaalkyl-C(O)—NH—. As used herein, the term “alkylsulfonyl” refers to agroup having the formula alkyl-SO₂—.

A sulfamoyl is a group having the formula NH₂S(O)₂—. The termN-alkylsulfamoyl is a sulfamoyl group in which one of the hydrogen atomsis replaced with an alkyl group. The term N,N-dialkylsulfamoyl is asulfamoyl group in which each hydrogen atoms is replaced with an alkylgroup which may be the same or different.

The term “alkylsulfonamido” refers to a group having the formulaalkyl-S(O)₂—NH—.

The term “trialkylsilyl” refers to (alkyl)₃-Si—, wherein each of thealkyl groups may be the same or different.

The number of carbon atoms in a group is specified herein by the prefix“C_(x-xx)”, wherein x and xx are integers. For example, “C₁₋₄alkyl” isan alkyl group which has from 1 to 4 carbon atoms; C₁₋₆alkoxy is analkoxy group having from 1 to 6 carbon atoms; C₆₋₁₀aryl is an aryl groupwhich has from 6 to 10 carbon atoms; C₁₋₄haloalkyl is a haloalkyl groupwhich has from 1 to 4 carbon atoms; and N,N-di-C₁₋₆alkylamino is aN,N-dialkylamino group in which the nitrogen is substituted with twoalkyl groups each of which is independently from 1 to 6 carbon atoms.

The phrase “compound of the invention,” as used herein, refers tocompounds represented by formulae (I), (II), (IIa), (IIb), and (III),and any of the specific examples disclosed herein.

The disclosed compounds can contain one or more asymmetric centers inthe molecule. In accordance with the present disclosure any structurethat does not designate the stereochemistry is to be understood asembracing all the various optical isomers (e.g., diastereomers andenantiomers) in pure or substantially pure form, as well as mixturesthereof (such as a racemic mixture, or an enantiomerically enrichedmixture). It is well known in the art how to prepare such opticallyactive forms (for example, resolution of the racemic form byrecrystallization techniques, synthesis from optically-active startingmaterials, by chiral synthesis, or chromatographic separation using achiral stationary phase). The compounds can be isotopically-labeledcompounds, for example, compounds including various isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, orchlorine. The disclosed compounds may exist in tautomeric forms andmixtures and separate individual tautomers are contemplated. Inaddition, some compounds may exhibit polymorphism.

By way of clarity, compounds of the invention included all isotopes ofthe atoms present in formulae (I), (II), (IIa), (IIb), and (III) and anyof the examples or embodiments disclosed herein. For example, H (orhydrogen) represents any isotopic form of hydrogen including ¹H, ²H (D),and ³H (T); C represents any isotopic form of carbon including ¹²C, ¹³C,and ¹⁴C; O represents any isotopic form of oxygen including ¹⁶O, ¹⁷O and¹⁸O; N represents any isotopic form of nitrogen including ³N, ¹⁴N and¹⁵N; P represents any isotopic form of phosphorous including ³¹P and³²P; S represents any isotopic form of sulfur including ³²S and ³⁵S; Frepresents any isotopic form of fluorine including ¹⁹F and ¹⁸F; Clrepresents any isotopic form of chlorine including ³⁵Cl, ³⁷Cl and ³⁶Cl;and the like. In a preferred embodiment, compounds represented byformulae (I)-(III) and any of the examples or embodiments disclosedherein comprises isotopes of the atoms therein in their naturallyoccurring abundance. However, in certain instances, it is desirable toenrich one or more atom in a particular isotope which would normally bepresent in less abundance. For example, ¹H would normally be present ingreater than 99.98% abundance; however, a compound of the invention canbe enriched in ²H or ³H at one or more positions where H is present. Inparticular embodiments of the compounds of formulae (I)-(III), when, forexample, hydrogen is enriched in the deuterium isotope, the symbol “D”may be used to represent the enrichment in deuterium. In one embodiment,when a compound of the invention is enriched in a radioactive isotope,for example ³H and ¹⁴C, they may be useful in drug and/or substratetissue distribution assays. It is to be understood that the inventionencompasses all such isotopic forms which modulate S1P and/or ATXactivity.

Exemplary compounds represented by formula (I) which may be useful asS1P modulating agents and/or ATX modulating agents include:

-   4-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-tert-butylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[3.5]nonan-7-yl-oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)methylamino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   2-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic    acid;-   4-(((5-trifluoromethyl-6-(trans-4-tert-butylcyclohexexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((5-trifluoromethyl-6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)    bicyclo[2.2.2]octane-1-carboxylic acid;-   4-(((6-(cis-4-methylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cyclohexyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[5.5]undecan-3-yl-oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-methylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-isopropylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-methylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(heptyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-phenylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-ethylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-isopropylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(4,4-dimethylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-carboxylic    acid;-   4-(((6-(trans-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-isopropylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)-2-hydroxybicyclo[2.2.2]octane-1-acetic    acid;-   4-(((6-(4,4-dimethylcyclohexyloxy)napthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-(1,1-dimethylpropyl)cyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[3.5]nonan-7-yl-oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[5.5]undecan-3-yl-oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-isopropylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-(1,1-dimethylpropyl)cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-trifluoromethylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-ethylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[4.5]decan-8-yl-oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-phenylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-phenylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-phenylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-methylcyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-(trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(cis-4-(trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(trans-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[3.5]nonan-7-yl-oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[2.5]octan-6-yl-oxy)napthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-(((6-(spiro[2.5]octan-6-yl-oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic    acid;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyridine-2-yl)piperazine;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyridine-4-yl)piperazine;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-phenylpiperazine;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyrimidine-2-yl)piperazine;-   1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-phenylpiperidine;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyrimidine-2-yl)piperazine;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyrazine-2-yl)piperazine;-   4-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyridine-2-yl)piperazine;-   4-((6-(spiro[4.5]decan-8-yl-oxy)naphthalen-2-yl)methyl)-1-(pyridine-2-yl)piperazine;-   4-((6-(heptyloxy)naphthalen-2-yl)methyl)-1-(pyridine-2-yl)piperazine;-   4-((6-(cis-4-isopropylcyclohexyloxy)quinolin-2-yl)methyl)-1-(pyridine-2-yl)piperazine;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyridine-2-yl)-1,4-diazepane;-   1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-(pyrimidine-2-yl)piperidine;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyrimidine-2-yl)-1,4-diazepane;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyrimidine-4-yl)piperazine;-   4-((6-(cis-4-isopropylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyridine-2-yl)piperazine-   1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-(pyridine-2-yl)piperidine;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(pyridine-3-yl)piperazine;-   4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-1-(2-methylpyrimidine-4-yl)piperazine;-   3-(1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohex    anecarboxylic acid;-   3-(1-((6-(4,4-dimethylcyclohexyloxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(heptyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   4-(1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(cis-2-ethylcyclohexyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(cis-2-isopropylcyclohexyloxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(cis-2-ethylcyclohexyloxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(cis-2-isopropylcyclohexyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(4,4-dimethylcyclohexyloxy)napthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   3-(1-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic    acid;-   2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-2-aza-6-oxaspiro[3.3]heptane;-   7-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-2,7-diazaspiro[3.5]nonane;-   2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-6-hydroxy-2-azaspiro[3.3]heptane;-   1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-3-phenylazetidine;-   2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-2,7-diazaspiro[3.5]nonane;-   1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-3,3-di(hydroxymethyl)azetidine;-   7-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-2-oxa-7-azaspiro[3.5]nonane;-   8-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-3-oxo-2-aza-8-azaspiro[4.5]decane;-   4-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic    acid;-   4-(((5-trifluoromethyl-6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)amino)    bicyclo[2.2.1]heptane-1-carboxylic acid;-   3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.1]heptane-6-carboxylic    acid;-   3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylic    acid;-   3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic    acid;-   8-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid; or-   9-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid.

Additional exemplary compounds represented by formula (I) which may beuseful as ATX modulating agents and/or S1P modulating agents include:

-   8-((5-difluoromethyl-6-(cis-4-trifluoromethycyclohexyloxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(2-(5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)acetyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(2-(5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)acetyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   2-(5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-oyl)decahydroisoquinolin-8-carboxylic    acid;-   9-(5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-oyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(5-trifluoromethyl-6-(cis-4-methcyclohexyloxy)naphthalen-2-oylcyclo[3.2.1]octane-3-carboxylic    acid;-   9-(2-(5-trifluoromethyl-6-(trans-(cis-3,5-dimethyl)cyclohexyloxy)naphthalen-2-yl)acetyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-oyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalene-2-yl)methyl)amino)bicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(1-(5-trifluoromethyl-6-(cis-4-methylcyclohexyloxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(5-trifluoromethyl-6-(cis-4-methylcyclohexyloxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   1-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalene-2-yl)methyl)4-imidazol-4-yl-piperidine;-   8-((5-trifluoromethyl-6-(cis-4-methylcyclohexyloxy)naphthalene-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((5-trifluoromethyl-6-(cis-4-methylcyclohexyloxy)naphthalene-2-yl)methyl)-8-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   7-((5-trifluoromethyl-6-(cis-4-methylcyclohexyloxy)naphthalen-2-yl)methyl)-7-aza-10-oxaspiro[4.5]decane-3-carboxylic    acid;-   9-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)quinolin-2-yl)methyl)-9-aza    bicyclo[3.3.1]nonane-3-carboxylic acid;-   8-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)quinolin-2-yl)methyl)-8-aza    bicyclo[3.2.1]octane-3-carboxylic acid;-   3-(1-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-yl)cyclohexane-1-carboxylic    acid;-   3-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-7-carboxylic    acid;-   2-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)-2-aza-6-oxaspiro[3.4]octane-7-carboxylic    acid;-   8-((5-trifluoromethyl-6-(4,4-difluorocyclohexyloxyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((5-trifluoromethyl-6-(4,4-difluorocyclohexyloxyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   3-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.0]octane-7-carboxylic    acid;-   3-(1-(((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalene-2-yl)methyl)methylamino)bicyclo[2.2.2]octan-4-yl)propionic    acid;-   3-(((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalene-2-yl)methyl)amino)adamantyl-1-carboxylic    acid;-   1-(((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalene-2-yl)methyl)amino)bicyclo[2.2.1]heptane-4-carboxylic    acid;-   3-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylic    acid;-   2-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)decahydroisoquinolin-8-carboxylic    acid;-   5-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)-5-azaspiro[2.3]hexane-1-carboxylic    acid;-   9-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-((5-trifluoromethyl-6-(cis-4-trifluoromethycyclohexyloxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-2-carboxylic    acid;-   3-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic    acid;-   1-(5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-oyl)amino-2,3-dihydroindene-6-carboxylic    acid;-   3-(1-(((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octan-4-yl)propionic    acid;-   2-((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalen-2-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylic    acid;-   (7R,9aR)-2-((2-(trans-4-(trifluoromethyl)cyclohexyloxy)-1-(trifluoromethyl)naphthalen-6-yl)methyl)-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic    acid;-   1-(((5-trifluoromethyl-6-(cis-4-trifluoromethylcyclohexyloxy)naphthalene-2-yl)methyl)amino)bicyclo[2.2.2]octane-4-carboxylic    acid; methyl-   (7R,9aR)-2-((2-(trans-4-(trifluoromethyl)cyclohexyloxy)-1-(trifluoromethyl)naphthalen-6-yl)methyl)-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylate;-   8-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)    naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   8-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid; 8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)    naphthalen-2-yl)ethyl)-8-azabicyclo[13.2.1]octane-3-carboxylic acid;-   8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[13.2.1]octane-3-carboxylic    acid;-   2-((trans-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carboxylic    acid;-   9-(2-((trans-4-(tert-butyl)cyclohexyl)amino)    quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;-   9-((3-((cis-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;    8-((4-chloro-3-((cis-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-8-azabicyclo[13.2.1]octane-3-carboxylic    acid;-   8-(3-((trans-4-(tert-butyl)cyclohexyl)amino)isoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)    isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((8-bromo-7-((cis-4-ethylcyclohexyl)oxy)    isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)    cyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)amino)bicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-((5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;    8-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoro-methyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-(1-(5-cyano-6-(((1s,4s)-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid; methyl-   8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylate;-   8-((r)-1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)    naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   8-((s)-1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)    naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   8-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)    naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   9-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;    9-((R)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((S)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-((R)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((S)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid; methyl-   9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate;    methyl-   9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate;-   8-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid; methyl    8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylate;-   8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(2-((cis-4-(tert-butyl)cyclohexyl)amino)    quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;-   8-((3-((trans-4-methylcyclohexyl)amino)    isoquinolin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(2-((cis-4-(tert-butyl)cyclohexyl)amino)    quinazoline-6-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   8-(2-((trans-4-methylcyclohexyl)amino)    quinazoline-6-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   9-((3-((trans-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-((4-chloro-3-((trans-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(3-(((1s,4s)-4-methylcyclohexyl)amino)    isoquinoline-7-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(3-((cis-4-methylcyclohexyl)amino)    isoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(2-((trans-4-(tert-butyl)cyclohexyl)amino)    quinazoline-6-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   9-(3-((trans-4-methylcyclohexyl)amino)isoquinoline-7-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(3-((trans-4-methylcyclohexyl)amino)    isoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-(2-((trans-4-methylcyclohexyl)amino)    quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;-   9-(2-((cis-4-methylcyclohexyl)amino)    quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;-   9-((4-chloro-3-((trans-4-methylcyclohexyl)    amino)isoquinolin-7-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(3-((cis-4-(tert-butyl)cyclohexyl)amino)isoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(2-((cis-4-methylcyclohexyl)amino)quinazoline-6-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((3-((cis-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((4-chloro-3-((cis-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-(3-((cis-4-(tert-butyl)cyclohexyl)amino)-4-chloroisoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-(3-((trans-4-(tert-butyl)cyclohexyl)amino)-4-chloroisoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((8-bromo-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)    isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-((8-bromo-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-3-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((8-bromo-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid; 8-((6-((cis-   4-ethylcyclohexyl)oxy)quinolin-2-yl)amino)bicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((8-bromo-7-((cis-4-methylcyclohexyl)oxy)    isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)amino)bicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((5-chloro-6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)amino)bicyclo[3.3.1]nonane-3-carboxylic    acid;-   (1R,3    S,5S)-9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3,7-dicarboxylic    acid;-   9-(1R,3S,5S,7s)-2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-azaadamantane-5-carboxylic    acid;-   9-(1R,3R,5S)-7-amino-9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)    naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;-   9-((6-(bicyclo[3.1.0]hexan-3-yloxy)-5-(trifluoromethyl)    naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;-   8-((6-(bicyclo[3.1.0]hexan-3-yloxy)-5-(trifluoromethyl)    naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   8-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   8-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic    acid;-   9-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   8-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)    naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   8-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)    naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;-   9-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic    acid;-   9-((R)-1-(6-(((1s,4S)-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)    naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;-   9-((S)-1-(6-(((1s,4R)-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)    naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;-   4-(2-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-2H-tetrazol-5-yl)piperidine;-   9-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carbonitrile;    or-   8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carbonitrile.

Compounds of the invention can modulate the activity of S1P receptors. Acompound of the invention can have S1P receptor agonist or antagonistactivity. The compound can be selective for the S1P4 receptor. Thecompound can be a selective S1P4 antagonist. Being selective can meanthat the compound binds to the receptor (or relatively small group ofrelated molecules or proteins) in a complex mixture, or in other words,when exposed to a variety of closely related receptor types, thecompound can bind preferentially to just one of the receptor types.

The compound can have a greater affinity for the S1P4 receptor, by at byat least 100-fold, by at least 50-fold, by at least 10-fold, by at least5-fold or by at least 2-fold, than for S1P1 receptor, S1P2 receptor,S1P3 receptor, or S1P5 receptor.

An inhibitor of S1P4 mediated activity can block S1P interaction with anS1P4 receptor. For example, the inhibitor can be an antagonist of anS1P4 receptor. An antagonist can be a molecule that has affinity for thereceptor but does not induce activity or a specific activity from thereceptor. The antagonist can bind with an S1P4 receptor with an IC₅₀value of less than 1 μM, less than 750 nM, less than 500 nM, less than250 nM or less than 100 nM. The antagonist can bind with an S1P4receptor with an IC₅₀ value in a range between 1 nM and 1 μM, between 1nM and 500 nM, between 10 nM and 250 nM, between 25 nm and 100 nM, orbetween 50 nM and 100 nM.

The compounds can also promote oligodendrocyte progenitor celldifferentiation. The compounds can promote myelination or remyelination.

An “S1P modulating agent” refers a compound or composition that iscapable of inducing a detectable change in S1P receptor activity in vivoor in vitro (e.g., at least 10% increase or decrease in S1P activity asmeasured by a given assay such as the assays described in the examplesand known in the art. “S1P receptor,” refers to all of the S1P receptorsubtypes (for example, the S1P receptors S1P1, S1P2, S1P3, S1P4, orS1P5), unless the specific subtype is indicated. It is well known in theart how to determine S1P agonist or antagonist activity using thestandard tests described herein, or using other similar tests which arewell known in the art. In some cases, depending on the cell type andconditions used, an S1P modulating agent can have agonist or antagonistactivity, even at the same receptor subtype.

The biological effects of an S1P modulating agent vary depending onwhether the compound has S1P receptor agonist or antagonist activity.Potential uses of an S1P modulating agent include, but are not limitedto, prevention or treatment of a pathological condition or symptom in amammal. For example, the condition can include asthma, an inflammatoryneuropathies, arthritis, lupus erythematosis, psoriasis, an ischemiareperfusion injury, a solid tumor, a tumor metastasis, a diseaseassociated with angiogenesis, a vascular disease, a pain condition, anacute viral disease, or insulin-dependent diabetes, and non-insulindependent diabetes. The condition can alter lymphocyte trafficking as amethod of treatment for neuropathic pain, inflammation-induced pain(e.g., where prostaglandins are involved) or treatment of autoimmunepathologies such as uveitis, type I diabetes, rheumatoid arthritis,chronic inflammatory disorders, inflammatory bowel diseases (e.g.,Crohn's disease and ulcerative colitis), multiple sclerosis, and indrug-eluting stents. Additional uses can include treatment of braindegenerative diseases, heart diseases, cancers, or hepatitis C. See, forexample, WO 2005/085295, WO 2004/010987, WO 03/097028, and WO2006/072562, each of which is incorporated by reference in its entirety.A class of S1P receptor agonists are described in provisional U.S.Application No. 60/956,111, filed Aug. 15, 2007, and PCT/US2008/073378,filed Aug. 15, 2008, each of which is incorporated by reference in itsentirety. See also provisional U.S. Application No. 61/231,539, filedAug. 5, 2009, and PCT/US2010/44607, filed Aug. 5, 2010, each of which isincorporated by reference in its entirety. See also provisional U.S.Application No. 61/440,254, filed Feb. 7, 2011, and PCT/US2012/23799filed Feb. 6, 2012, each of which is incorporated by reference in itsentirety.

Additional potential uses of an S1P modulating agent include, but arenot limited to, prevention or treatment of a pathological condition orsymptom in a mammal. For example, the condition can include inhibitedcell migration of oligodendrocyte precursor cells (OPCs).

Potential uses of an S1P receptor antagonist, and S1P4 receptor typeselective antagonists particularly, include, but are not limited to,prevention or treatment of a pathological condition or symptom in amammal.

LPA has been shown to be involved in lymphocyte trafficking and helpspromote entry of lymphocytes into secondary lymphoid organs (see Kanda,et al., Nat. Immunology (2008), 9:415-423). Therefore, the disclosedcompounds are expected to be useful for altering lymphocyte traffickingas a method for prolonging allograft survival, for exampletransplantation including solid organ transplants, treatment of graftvs. host disease, bone marrow transplantation, and the like.

An “ATX modulating agent” refers a compound or composition that iscapable of inducing a detectable change in ATX activity in vivo or invitro (e.g., at least 10% increase or decrease in ATX activity asmeasured by a given assay such as the assays described in the examplesand known in the art. A compound of the invention be an ATX modulatingagent, i.e., it can modulate the activity of ATX. For example, acompound of the invention can be an ATX inhibitor. The compound can be aselective ATX modulating agent. Being selective can mean that thecompound binds to ATX preferentially when exposed to a variety ofpotential binding partners. The compound can have a greater affinity forthe ATX, by at by at least 100-fold, by at least 50-fold, by at least10-fold, by at least 5-fold or by at least 2-fold, than for otherbinding partners. Affinity can be measured, for example, as adissociation constant (K_(d)), as an inhibition constant (such as IC₅₀),or another measure; provided that affinity is measured in a consistentfashion between ATX and the other binding partners it is compared to.

An inhibitor of ATX mediated activity can block interaction of ATX withits native substrate(s), such as LPC. For example, the inhibitor canshow an IC₅₀ value of less than 1 μM, less than 750 nM, less than 500nM, less than 250 nM, less than 100 nM, less than 50 nM, less than 25nM, or less than 10 nM, when measured in a FRET-based assay using FS-3substrate (see, e.g., Ferguson, C. G., et al., Org Lett. 2006 May 11;8(10): 2023-2026, which is incorporated by reference in its entirety).

Some substrates and inhibitors of ATX are described in WO 2011/151461,which is incorporated by reference in its entirety.

Potential uses of an ATX modulating agent include, but are not limitedto, prevention or treatment of a pathological condition or symptom in amammal. The pathological disorder can be an inflammatory disorder, anautoimmune disorder, a fibrosis of the lung, or a malignancy of thelung. Prevention or treatment of the pathological condition or symptomcan include administering to the mammal an effective amount of an ATXmodulating agent, e.g., an ATX inhibitor, to prevent, treat or reducesymptoms of the inflammatory disorder, autoimmune disorder, the fibrosisof the lung, or the malignancy of the lung. In one embodiment, theinflammatory disorder is rheumatoid arthritis (RA). In anotherembodiment, the autoimmune disorder is multiple sclerosis (MS). Aparticular example of lung fibrosis is an interstitial lung disease, forinstance, pulmonary fibrosis. See, for example, WO 2011/151461, which isincorporated by reference in its entirety.

In some embodiments, an ATX inhibitor of the present invention can beused to treat or prevent a demyelinating disease or disorder.Demyelinating diseases or disorders include multiple sclerosis,Guillain-Barre Syndrome, chronic inflammatory demyelinatingpolyneuropathy (CIDP), transverse myelitis, and optic neuritis, spinalcord injury, stroke or other ischemia, cerebral palsy,Charcot-Marie-Tooth disease (CMT), Sjogren-Larsson syndrome, Refsumdisease, Krabbe disease, Canavan disease, Alexander disease, nervedamage due to pernicious anemia, progressive multifocalleukoencephalopathy (PML), Lyme disease, tabes dorsalis due to untreatedsyphilis, demyelination due to exposure to an organophosphates,demyelination due to vitamin B12 deficiency or copper deficiency.

In addition, disclosed compounds can be useful as antagonists of thecannabinoid CB₁ receptor. CB₁ antagonism is associated with a decreasein body weight and an improvement in blood lipid profiles. The CB₁antagonism could be in concert with S1P receptor activity, or beindependent of activity at any S1P receptor.

In addition, disclosed compounds can be useful for inhibition of groupIVA cytosolic PLA₂ (cPLA₂). cPLA₂ catalyzes the release of eicosanoicacids (e.g., arachidonic acid). The eicosanoic acids are transformed topro-inflammatory eicosanoids such as prostaglandins and leukotrienes.Thus, disclosed compounds may be useful as anti-inflammatory agents.This inhibition could be in concert with S1P receptor activity, or beindependent of activity at any S1P receptor.

In addition, disclosed compounds may be useful for inhibition of themultiple substrate lipid kinase (MuLK). MuLK is highly expressed in manyhuman tumor cells and thus its inhibition might slow the growth orspread of tumors.

Neurological Disorders

MS can begin with a relapsing-remitting pattern of neurologicinvolvement, which then can progress to a chronic phase with increasingneurological damage. MS can be associated with the destruction ofmyelin, oligodendrocytes or axons localized to chronic lesions. Thedemyelination observed in MS may not always permanent and remyelinationhas been documented in early stages of the disease. Remyelination ofneurons can require oligodendrocytes.

The distal tip of an extending axon or neurite can include a specializedregion, known as the growth cone. Growth cones can sense the localenvironment and can guide axonal growth toward a neuron's target cell.Growth cones can respond to environmental cues, for example, surfaceadhesiveness, growth factors, neurotransmitters and electric fields. Thegrowth cones can advance at a rate of one to two millimeters per day.The growth cone can explore the area ahead of it and on either side, bymeans of elongations classified as lamellipodia and filopodia. When anelongation contacts an unfavorable surface, it can withdraw. When anelongation contacts a favorable growth surface, it can continue toextend and guides the growth cone in that direction. When the growthcone reaches an appropriate target cell a synaptic connection can becreated.

Nerve cell function can be influenced by contact between neurons andother cells in their immediate environment (Rutishauser, et al., 1988,Physiol. Rev. 68:819, which is incorporated by reference in itsentirety). These cells can include specialized glial cells,oligodendrocytes in the central nervous system (CNS), and Schwann cellsin the peripheral nervous system (PNS), which can sheathe the neuronalaxon with myelin (Lemke, 1992, in An Introduction to MolecularNeurobiology, Z. Hall, Ed., p. 281, Sinauer, each of which isincorporated by reference in its entirety). LPA causes the collapse ofthe neuron growth cone and tends to inhibit or reverse the morphologicaldifferentiation of many neuronal cell lines (see Gendaszewska-Darmach,Acta Biochimica Polonica (2008), 55(2):227-240). Since ATX activity isinvolved in the generation of LPA, inhibitors of ATX should increase theability of the nervous system to make synaptic connections. Thus, ATXinhibitors may be useful in treating neurodegenerative disorders such asAlzheimer's disease, Huntington's disease, Parkinson's disease(including Parkinson's dementia), Lewy Body Dementia, amylotrophiclateral sclerosis (ALS), Friedreich's ataxia, spinal muscular atrophy.

CNS neurons can have the inherent potential to regenerate after injury,but they can be inhibited from doing so by inhibitory proteins presentin myelin (Brittis et al., 2001, Neuron 30:11-14; Jones et al., 2002, J.Neurosci. 22:2792-2803; Grimpe et al., 2002, J. Neurosci.: 22:3144-3160,each of which is incorporated by reference in its entirety).

Several myelin inhibitory proteins found on oligodendrocytes have beencharacterized. Known examples of myelin inhibitory proteins can includeNogoA (Chen et al., Nature, 2000, 403, 434-439; Grandpre et al., Nature2000, 403, 439-444, each of which is incorporated by reference in itsentirety), myelin associated glycoprotein (MAG) (McKerracher et al.,1994, Neuron 13:805-811; Mukhopadhyay et al., 1994, Neuron 13:757-767,each of which is incorporated by reference in its entirety) oroligodendrocyte glycoprotein (OM-gp), Mikol et al., 1988, J. Cell. Biol.106:1273-1279, each of which is incorporated by reference in itsentirety). Each of these proteins can be a ligand for the neuronal Nogoreceptor-1(NgR1 (Wang et al., Nature 2002, 417, 941-944; Grandpre etal., Nature 2000, 403, 439-444; Chen et al., Nature, 2000, 403, 434-439;Domeniconi et al., Neuron 2002, published online Jun. 28, 2002, each ofwhich is incorporated by reference in its entirety).

Nogo receptor-1(NgR1) is a GPI-anchored membrane protein that contains 8leucine rich repeats (Fournier et al., 2001, Nature 409:341-346, whichis incorporated by reference in its entirety). Upon interaction withinhibitory proteins (e.g., NogoA, MAG and OM-gp), the NgR1 complex cantransduce signals that lead to growth cone collapse and inhibition ofneurite outgrowth.

There is a need for molecules and methods for inhibiting NgR1-mediatedgrowth cone collapse and the resulting inhibition of neurite outgrowth.Additionally, there is a need for molecules which increase neuronalsurvival and axon regeneration, particularly for the treatment ofdisease, disorders or injuries that involve axonal injury, neuronal oroligodendrocyte cell death, demyelination or dymyelination or generallyrelate to the nervous system.

Such diseases, disorders or injuries can include, but are not limitedto, multiple sclerosis (MS), progressive multifocal leukoencephalopathy(PML), encephalomyelitis (EPL), central pontine myelolysis (CPM),adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease(PMZ), Globoid cell Leucodystrophy (Krabbe's disease) and WallerianDegeneration, optic neuritis, transverse myelitis, amylotrophic lateralsclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson'sdisease, spinal cord injury, traumatic brain injury, post radiationinjury, neurologic complications of chemotherapy, stroke, acute ischemicoptic neuropathy, vitamin E deficiency, isolated vitamin E deficiencysyndrome, AR, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome,metachromatic leukodystrophy, trigeminal neuralgia, or Bell's palsy.Among these diseases, MS may the most widespread, affectingapproximately 2.5 million people worldwide.

Various disease-modifying treatments may be available for MS, includingthe use of corticosteroids and immunomodulating agents such asinterferon beta or Tysabri®. In addition, because of the central role ofoligodendrocytes and myelination in MS, there have been efforts todevelop therapies to increase oligodendrocyte numbers or enhancemyelination. See, e.g., Cohen et al., U.S. Pat. No. 5,574,009; Chang etal., N. Engl. J. Med. 346: 165-73 (2002), each of which is incorporatedby reference in its entirety. However, there remains an urgent need todevise additional therapies for MS and other demyelination anddismyelination disorders.

A compound of the invention, or a pharmaceutically acceptable saltthereof, can promote myelination or remyelination. A method can includeadministering a compound of the invention, or a pharmaceuticallyacceptable salt thereof, to cells. A method of promoting oligodendrocyteprogenitor cell differentiation can include administering a compound ofthe invention, or a pharmaceutically acceptable salt thereof, to cells.A method of treating multiple sclerosis can include administering acompound of the invention, or a pharmaceutically acceptable saltthereof, to a subject.

A number of studies have shown that ATX is expressed in non-pathologicalconditions, throughout development, with high expression levels in theCNS among other tissues. ATX mRNA was identified as highly upregulatedduring oligodendrocyte differentiation and ATX protein expression isalso apparent in maturing ODCs, temporally correlated with the processof myelination. Finally, in the adult brain ATX is expressed insecretory epithelial cells, such as the choroid plexus, ciliary, irispigment, and retinal pigment epithelial cells, whereas there is evidencefor ATX expression in leptomenigneal cells and cells of the CNSvasculature. See, for example, Fuss, B., et al., J Neurosci 17,9095-9103 (1997); Kawagoe, H., et al. Genomics 30, 380-384 (1995); Lee,H. Y., et al. J Biol Chem 271, 24408-24412 (1996); Narita, M., et al., JBiol Chem 269, 28235-28242 (1994); Bachner, D., et al., Mechanisms ofDevelopment 84, 121-125 (1999); Awatramani, R., et al., Nat Genet 35,70-75 (2003); Li, Y., et al., J Neurol Sci 193, 137-146 (2002); Dugas,J. C., et al., J Neurosci 26, 10967-10983 (2006); Fox, M. A., et al.,Molecular and Cellular Neuroscience 27, 140-150 (2004); Hoelzinger, D.B., et al., Neoplasia 7, 7-16 (2005); and Sato, K., et al., J Neurochem92, 904-914 (2005); each of which is incorporated by reference in itsentirety.

Although neurons and astrocytes do not seem to express ATX underphysiological conditions, ATX is highly upregulated in astrocytesfollowing brain lesion. Two hallmarks of reactive astrogliosis can beinduced by LPA itself: hypertrophy of astrocytes and stress fiberformation. This may indicate an autoregulation loop of astrocyticactivation, in which astrocytes upregulate the LPA-generating enzyme ATXand become activated by its metabolite LPA, while increased amounts ofthe metabolite inhibit the catalytic activity of ATX. See, e.g.,Savaskan, N. E., et al., Cell Mol Life Sci 64, 230-243 (2007); Ramakers,G. J, & Moolenaar, W. H., Exp Cell Res 245, 252-262 (1998); and vanMeeteren, L. A., et al., J Biol Chem 280, 21155-21161 (2005); each ofwhich is incorporated by reference in its entirety.

ATX expression levels were shown to be elevated in glioblastomamultiform samples, and ATX was shown to augment invasiveness of cellstransformed with ras, a key signaling molecule that promotesgliomagenesis. ATX expression was also detected in primary tumor tissuesfrom neuroblastoma patients and retinoic acid induced expression of ATXin N-myc-amplified neuroblastoma cells.

There is significant evidence for ATX signaling in demyelinationprocesses and in other neurodegenerative conditions. As noted above, ithas been reported that addition of LPA to dorsal root fibers in ex vivoculture causes demyelination, whereas LPC fails to cause significantdemyelination of nerve fibers in ex vivo cultures without furtheraddition of recombinant ATX to the culture. Addition of recombinant ATXcaused significant demyelination at equivalent levels to LPA presumabledue to conversion of LPC to LPA through the enzymatic activity of ATX.In addition, injury induced demyelination was attenuated by about 50% inatx^(+/−) mice over their wild type counterparts (Nagai, et al.,Molecular Pain (2010), 6:78).

ATX protein levels were found deregulated in an animal model of MS(experimental autoimmune encephalitis; EAE) at the onset of clinicalsymptoms. See, e.g., Hoelzinger, D. B., et al. Neoplasia 7, 7-16 (2005);Nam, S. W., et al., Oncogene 19, 241-247 (2000); Kawagoe, H., et al.,Cancer Res 57, 2516-2521 (1997); Dufner-Beattie, J., et al., MolCarcinog 30, 181-189 (2001); Umemura, K., et al., Neuroscience Letters400, 97-100 (2006); and Fuss, B., et al., J Neurosci 17, 9095-9103(1997); each of which is incorporated by reference in its entirety.Moreover, significant ATX expression was been detected in thecerebrospinal fluid of patients suffering with multiple sclerosis (MS),while completely lacking from the control samples, suggesting a role forATX in maintenance of cerebrospinal fluid homeostasis duringpathological/demyelinating conditions. Hammack, B. N., et al. Proteomicanalysis of multiple sclerosis cerebrospinal fluid. Mult Scler 10,245-260 (2004); and Dennis, J., et al., J Neurosci Res 82, 737-742(2005); each of which is incorporated by reference in its entirety.

Interestingly, ATX mRNA expression was found to be elevated in thefrontal cortex of Alzheimer-type dementia patients indicating apotential involvement for ATX signaling in neurodegenerative diseases.LPA receptors are enriched in the CNS and their expression patternssuggest their potential involvement in developmental process includingneurogenesis, neuronal migration, axon extension and myelination.Noteworthy, only two receptors have the same spatiotemporal expressionas ATX in the CNS (Contos, J. J., et al., Mol Cell Biol 22, 6921-6929(2002); Jaillard, C, ei al, Edg8/S1P5: an oligodendroglial receptor withdual function on process retraction and cell survival. J Neurosci 25,1459-1469 (2005); and Saba, J. D. Journal of cellular biochemistry 92,967-992 (2004); each of which is incorporated by reference in itsentirety). LPAi and SIPS are specific for ODCs, and their expressionhighly correlates with the process of myelination. LPA1 is expressed inrestricted fashion within the neuroblasts of the neuroproliferatveVentricular Zone (VZ) of the developing cortex, in the dorsal olfactorybulb, along the pial cells of neural crest origin, and in developingfacial bone tissue. Expression is observed during E11-E18, correspondingto a time period during which neurogenesis occurs. LPA1 expression isundetectable in the VZ after this point, to reappear during the firstpostnatal week within ODCs. Notably, Schwann cells (the myelinatingcells of the Peripheral Nervous System; PNS) express high levels of LPA1early in development and persistently throughout life, suggesting aninfluence of LPA on myelinating processes (Weiner. J. A. & Chun, J.,Proc Natl Acad Sci USA 96, 5233-5238 (1999), which is incorporated byreference in its entirety).

The above data strongly support a critical role for ATX and LPAsignaling in neuronal development, oligodendrocyte differentiation andmyelination, as well as possibly in the autoregulation of astrocyteactivation. Moreover, the regulation of ATX and thus LPA production atlocal sites of CNS injury, inflammatory or autoimmune, could contributeto tissue homeostasis through the numerous effects of LPA. Asdemyelination and deregulated cerebrospinal fluid homeostasis are thehallmarks of multiple sclerosis, a role of ATX and LPA signaling in thepathophysiology of multiple sclerosis seems very likely.

The S1P modulating agents and/or ATX modulating agents of the inventioncan be used to various forms of MS including relapsing-remitting,secondary-progressive, primary-progressive, and progressive-relapsingforms. In addition, S1P modulating agents and/or ATX modulating agentsof the invention can be used alone or in conjunction with other agentsto treat or prevent MS. In a preferred embodiment, the compounds of theinvention can be used to treat or prevent MS in combination with animmunomodulating therapy such as corticosteroids, beta interferon-1a(such as Avonex® or Rebif®), beta interferon-1b (Betaseron®),natalizumab (Tysabri®), glatiramer, and mitoxantrone.

Pain Mediation

Pain experienced by mammals can be divided into two main categories:acute pain (or nociceptive) and chronic pain which can be subdividedinto chronic inflammatory pain and chronic neuropathic pain. Acute painis a response to stimulus that causes tissue injury and is a signal tomove away from the stimulus to minimize tissue damage. Chronic pain, onthe other hand, serves no biological function and develops as a resultof inflammation caused by tissue damage (inflammatory pain) or by damageto the nervous system such as demyelination (neuropathic pain). Chronicpain is generally characterized by stimulus-independent, persistent painor by abnormal pain perception triggered by innocuous stimuli.

LPA has been found to be a mediator of both inflammatory pain andneuropathic pain. The transient receptor potential channel TRPV1 isknown to be the originator of inflammatory pain. LPA has been shown todirectly activate TRPV1 thereby creating pain stimulus by binding to itsintracellular C-terminus (Tigyi, Nature Chemical Biology (January 2012),8:22-23). Thus, compounds which inhibit the formation of LPA byinhibiting the action of ATX would be useful in treating inflammatorypain.

LPA has also been shown to play a role in neuropathic pain. For example,sciatic nerve injury has been shown to induce demyelination,down-regulation of myelin-associated glycoprotein (MAG) and damage toSchwann cell partitioning of C-fiber-containing Remak bundles in thesciatic nerve and dorsal root. However, demyelination, MAGdown-regulation and Remak bundle damage in the dorsal root wereabolished in LPA₁ receptor-deficient (Lpar1^(−/−) mice (Nagai, et al.,Molecular Pain (2010), 6:78). These results indicate that compounds thatinhibit the formation of LPA by inhibiting the action of ATX woulddecrease dorsal root demyelination following nerve injury and decreaseor eliminate neuropathic pain.

Thus the compounds of the invention are useful in treating or preventingchronic pain such as inflammatory pain and neuropathic pain in mammals.

Rheumatoid Arthritis (RA)

Studies in human and animal models of RA suggest that ATX plays a rolein the development and progress of the disease. For example, increasedATX mRNA expression was detected in synovial fibroblasts (SFs) fromanimal models of RA during differential expression profiling, and humanRA SFs were shown to express mRNA for both ATX and LPARs (Aidinis, V.,et al., PLoS genetics 1, e48 (2005); Zhao, C, et al., Molecularpharmacology 73, 587-600 (2008); each of which is incorporated byreference in its entirety). ATX is overexpressed from activated SFs inarthritic joints, both in animal models and human patients (see WO2011/151461). ATX expression was shown to be induced from TNF, the majorpro-inflammatory factor driving RA.

Disease development was assessed in well-established animal models ofRA. When ATX expression was conditionally ablated specifically in SFs,the lack of ATX expression in the joints resulted in marked decreasedinflammation and synovial hyperplasia. This suggested an activeinvolvement of the ATX-LPA axis in the pathogenesis of the disease.Similar results were also obtained with pharmacologic inhibition of ATXenzymatic activity and LPA signaling. A series of ex vivo experiments onprimary SFs revealed that ATX, through LPA production, stimulatesrearrangements of the actin cytoskeleton, proliferation and migration tothe extracellular matrix (ECM), as well as the secretion ofproinflammatory cytokines and matrix metalloproteinases (MMPs).Moreover, the LPA effect was shown to be synergistic with TNF anddependent on the activation of MAPK cellular signaling pathways. See,e.g., Armaka, M., et al., The Journal of experimental medicine 205,331-337 (2008); which is incorporated by reference in its entirety.

In one embodiment a method for treating an individual with RA or theindividual at risk of suffering thereof comprises administering to saidindividual an S1P modulating agent and/or ATX modulating agent of theinvention in conjunction with an anti-TNF antibody for use in thetreatment of RA. Examples of suitable anti-TNF antibodies areadalimumab, etanercept, golimumab, and infliximab (Taylor P C, FeldmannM. Anti-TNF biologic agents: still the therapy of choice for rheumatoidarthritis. Nat Rev Rheumatol. 2009 October; 5(10):578-82).

Pulmonary Fibrosis

Evidence also suggests a role for ATX in pulmonary fibrosis. Micelacking lysophosphatidic acid (LPA) receptor 1(LPAR1) were protectedfrom Bleomycin (BLM)-induced pulmonary fibrosis and mortality,suggesting a major role for LPA in disease pathophysiology. The majorityof circulating LPA is produced by the phospholipase D activity ofAutotaxin (ATX) and the hydrolysis of lysophosphatidylcholine (LPC).Increased ATX expression has been previously reported in thehyperplastic epithelium of fibrotic lungs of human patients and animalmodels.

Therefore, we hypothesized that genetic or pharmacologic inhibition ofATX activity would reduce local or circulating LPA levels and henceattenuate disease pathogenesis.

Lung Cancer

Increased ATX expression has been detected in a large number ofmalignancies, including mammary, thyroid, hepatocellular and renal cellcarcinomas, glioblastoma and neuroblastoma, as well as NSCLC.Strikingly, transgenic overexpression of ATX was shown to inducespontaneous mammary carcinogenesis. In accordance, in vitro ATXoverexpression in various cell types promotes proliferation andmetastasis while inhibiting apoptosis. LPA's actions are concordant withmany of the “hallmarks of cancer”, indicating a role for LPA in theinitiation or progression of malignant disease. Indeed LPA levels aresignificantly increased in malignant effusions, and its receptors areaberrantly expressed in several human cancers. See, for example: Euer,N., et al., Anticancer Res 22, 733-740 (2002); Liu, S., et al., CancerCell 15, 539-550 (2009); Zhang, G., et al., Chin Med J (Engl) 112,330-332 (1999); Stassar, M. J., et al., Br J Cancer 85. 1372-1382(2001); Kishi, Y., et al., J Biol Chem 281, 17492-17500 (2006); Kawagoe,H., et al., Cancer Res 57, 2516-2521 (1997); Yang, Y., et al., Am JRespir Cell Mol Biol 21, 216-222 (1999); and Toews, M. L., et al.Biochim Biophys Acta 1582, 240-250 (2002); each of which is incorporatedby reference in its entirety.

In cases where a compound of the invention can be sufficiently basic oracidic to form stable nontoxic acid or base salts, preparation andadministration of the compounds as pharmaceutically acceptable salts maybe appropriate. Examples of pharmaceutically acceptable salts can beorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, or α-glycerophosphate. Inorganic salts may also beformed, including hydrochloride, sulfate, nitrate, bicarbonate, andcarbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

Pharmaceutically-acceptable base addition salts can be prepared frominorganic and organic bases. Salts from inorganic bases, can include butare not limited to, sodium, potassium, lithium, ammonium, calcium ormagnesium salts. Salts derived from organic bases can include, but arenot limited to, salts of primary, secondary or tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl)amines, tri(substituted alkenyl)amines,cycloalkyl amines, di(cycloalkyl)amines, tri(cycloalkyl)amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines,di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substitutedcycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstitutedcycloalkenyl amines, aryl amines, diaryl amines, triaryl amines,heteroaryl amines, diheteroaryl amines, triheteroaryl amines,heterocyclic amines, diheterocyclic amines, triheterocyclic amines, ormixed di- and tri-amines where at least two of the substituents on theamine can be different and can be alkyl, substituted alkyl, alkenyl,substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic and thelike. Also included can be amines where the two or three substituents,together with the amino nitrogen, form a heterocyclic or heteroarylgroup. Non-limiting examples of amines can include, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl)amine,tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, or N-ethylpiperidine, andthe like. Other carboxylic acid derivatives can be useful, for example,carboxylic acid amides, including carboxamides, lower alkylcarboxamides, or dialkyl carboxamides, and the like.

Pharmaceutical compositions can include a compound of the invention, ora pharmaceutically acceptable salt thereof. More particularly, suchcompounds can be formulated as pharmaceutical compositions usingstandard pharmaceutically acceptable carriers, fillers, solubilizingagents and stabilizers known to those skilled in the art. For example, apharmaceutical composition including a compound of the invention, or asalt, analog, derivative, or modification thereof, as described herein,is used to administer the appropriate compound to a subject.

The compounds of the invention, or a pharmaceutically acceptable saltthereof, are useful for treating a disease or disorder associated withS1P receptor activity, and/or ATX activity. In one embodiment, atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof, is administered to a subjectin need thereof. In another embodiment, a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, and apharmaceutically-acceptable carrier is administered to a subject in needthereof.

The compounds of the invention can be used in combination with at leastone further active ingredient, such as a medicament used in thetreatment of multiple sclerosis such as Tysabri®, dimethyl fumarate, aninterferon (such as pegylated or non-pegylated interferons, preferablyinterferon β-1a or pegylated interferon β-1a), glatiramer acetate, acompound improving vascular function, an immunomodulating agent (such asFingolimod, cyclosporins, rapamycins or ascomycins, or theirimmunosuppressive analogs, e.g. cyclosporine A, cyclosporine G, FK-506,ABT-281, ASM981, rapamycin, 40-O-(2-hydroxyl)ethyl-rapamycin etc.);corticosteroids; cyclophosphamide; azathioprine; mitoxanthrone,methotrexate; leflunomide; mizoribine; mycophenolic add; mycophenolatemofetil; 15-deoxyspergualine; diflucortolone valerate; difluprednate;Alclometasone dipropionate; amcinonide; amsacrine; asparaginase;azathioprine; basiliximab; beclometasone dipropionate; betamethasone;betamethasone dipropionate; betamethasone phosphate sodique;betamethasone valerate; budesonide; captopril; chlormethinechlorhydrate; clobetasol propionate; cortisone acetate; cortivazol;cyclophosphamide; cytarabine; daclizumab; dactinomycine; desonide;desoximetasone; dexamethasone; dexamethasone acetate; dexamethasoneisonicotinate; dexamethasone metasulfobenzoate sodique;dexamethasonephosphate; dexamethasone tebutate; dichlorisone acetate;doxorubicinee chlorhydrate; epirubicine chlorhydrate; flucloroloneacetonide; fludrocortisone acetate; fludroxycortide; flumetasonepivalate; flunisolide; fluocinolone acetonide; fluocinonide;fluocortolone; fluocortolone hexanoate; fluocortolone pivalate;fluorometholone; fluprednidene acetate; fluticasone propionate;gemcitabine chlorhydrate; halcinonide; hydrocortisone; hydrocortisoneacetate; hydrocortisone butyrate; hydrocortisone hemisuccinate;melphalan; meprednisone; mercaptopurine; methylprednisolone;methylprednisolone acetate; methylprednisolone hemisuccinate;misoprostol; muromonab-cd3; mycophenolate mofetil; paramethansoneacetate; prednazoline, prednisolone; prednisolone acetate; prednisolonecaproate; prednisolone metasulfobenzoate sodique; prednisolone phosphatesodique; prednisone; prednylidene; rifampicine; rifampicine sodique;tacrolimus; teriflunomide; thalidomide; thiotepa; tixocortol pivalate;triamcinolone; triamcinolone acetonide hemisuccinate; triamcinolonebenetonide; triamcinolone diacetate; triamcinolone hexacetonide;immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies toleukocyte receptors, e.g., MHC, CD2, CD3, CD4,CD7, CD20 (e.g., rituximaband ocrelizumab), CD25, CD28, B7, CD40, CD45, CD56 (e.g., daclizumab),or CD58 or their ligands; or other immunomodulating agenty compounds,e.g. CTLA41 g, or other adhesion molecule inhibitors, e.g. mAbs or lowmolecular weight inhibitors including Selectin antagonists and VLA-4antagonists (such as Tysabri®); remyelinating agents such as BIIB033.Compounds of the invention can also be used in combination with agentswhich treat the symptoms of multiple sclerosis such as fampridine.

The dose of a compound of the invention, or a pharmaceuticallyacceptable salt thereof, administered to a subject can be less than 10μg, less than 25 μg, less than 50 μg, less than 75 μg, less than 0.10mg, less than 0.25 mg, less than 0.5 mg, less than 1 mg, less than 2.5mg, less than 5 mg, less than 10 mg, less than 15 mg, less than 20 mg,less than 50 mg, less than 75 mg, less than 100 mg, or less than 500 mg.

Administering can include administering by topical, enteral, parenteral,transdermal, transmucosal, inhalational, intracisternal, epidural,intravaginal, intravenous, intramuscular, subcutaneous, intradermal orintravitreal administration. In addition, the term “administer” or“administering” encompasses delivering a compound of the invention as aprodrug which is converted or metabolized in the body of the mammal intoa compound of the invention. In one embodiment, a compound of theinvention is administered in a non-prodrug form. In another embodiment,the compound is administered as a prodrug which is metabolized to acompound of the invention in the body of a mammal.

The duration of administering can be less than 30 seconds, less than 1minute, about 1 minute, between 1 minute and 5 minutes, between 5minutes and 10 minutes, between 10 minutes and 20 minutes, between 20minutes and 30 minutes, between 30 minutes and 1 hour, between 1 hourand 3 hours, between 3 hours and 6 hours, between 6 hours and 12 hours,between 12 hours and 24 hours or for more than 24 hours.

Administering the inhibitor or compound can include multipleadministrations. The duration between administrations can be less than30 seconds, less than 1 minute, about 1 minute, between 1 minute and 5minutes, between 5 minutes and 10 minutes, between 10 minutes and 20minutes, between 20 minutes and 30 minutes, between 30 minutes and 1hour, between 1 hour and 3 hours, between 3 hours and 6 hours, between 6hours and 12 hours, between 12 hours and 24 hours or for more than 24hours.

The duration between successive administrations can be less than 30seconds, less than 1 minute, about 1 minute, between 1 minute and 5minutes, between 5 minutes and 10 minutes, between 10 minutes and 20minutes, between 20 minutes and 30 minutes, between 30 minutes and 1hour, between 1 hour and 3 hours, between 3 hours and 6 hours, between 6hours and 12 hours, between 12 hours and 24 hours, between 24 hours and48 hours, between 48 hours and 72 hours, between 72 hours and 1 week orbetween 1 week and 2 weeks.

Administering an inhibitor or compound to cells can include cells of anin vitro or in vivo system or model. The cells can be part of a cellline. The cell line can be a primary or secondary cell line. The cellline can be an immortal cell line. The cells can be ruptured and be inthe form of a cell lysate. The cells can be part of a living organism,i.e., a subject, for example, a mammal. A mammal can include a rat, amouse, a gerbil, a hamster, a rabbit or a human. The human can be asubject or a patient.

A method can further include monitoring a property of a sample or asubject. A sample can be removed from a subject. For instance, a samplecan include a sample of cells or a tissue from a subject. A sample caninclude blood, plasma, or neuronal tissue including neurons or glialcells. A sample can also remain in the subject. For example, a samplecan be a tissue or cells that are observed within the patient.

A method can further include providing untreated control cells, sampleor subject and measuring a property of a sample of the untreated controlcells, sample or subject.

A property can include the presence or absence of a molecule, theconcentration of a molecule, for example myelin basic protein, myelinassociated glycoprotein or myelin oligodendrocyte glycoprotein. In someembodiments, determining the presence of a molecule can includedetermining the concentration of the molecule, determining the purity ofthe molecule or determining the quantity of the molecule.

A property can be the conductivity of a tissue or cell. A property canbe an emission, for example, electromagnetic radiation.

Monitoring a property can include observing the property of the sampleor subject alone. Monitoring a property can include monitoring theproperty before the sample or subject has been administered a compoundof the invention. Monitoring a property can include monitoring theproperty after the sample or subject has been administered a compound.Monitoring a property can include monitoring a property after the sampleor subject has been administered a known concentration of a compound.

Monitoring a property of a sample or subject can include observing theproperty through a microscope. Monitoring a property of the compositioncan include measuring the property using a microscope. Monitoring aproperty of the composition can include monitoring the property usingstill photography or movies. The photography or movies can be on filmmedia or digital form. Monitoring a property can include taking a scan,for example, an MRI or CT scan.

Promoting myelination, remyelination or oligodendrocyte progenitor celldifferentiation can prevent or can treat a pathological condition orsymptom in a mammal. A number of diseases or disorders involvedemyelination of the central or peripheral nervous system which canoccur for a number of reasons such as immune dysfunction as in multiplesclerosis, encephalomyelitis, Guillain-Barre Syndrome, chronicinflammatory demyelinating polyneuropathy (CIDP), transverse myelitis,and optic neuritis; demyelination due to injury such as spinal cordinjury, traumatic brain injury, stroke, acute ischemic optic neuropathy,or other ischemia, cerebral palsy, neuropathy (e.g. neuropathy due todiabetes, chronic renal failure, hypothyroidism, liver failure, orcompression of the nerve), post radiation injury, and central pontinemyelolysis (CPM); inherited conditions such as Charcot-Marie-Toothdisease (CMT), Sjogren-Larsson syndrome, Refsum disease, Krabbe disease,Canavan disease, Alexander disease, Friedreich's ataxia,Pelizaeus-Merzbacher disease, Bassen-Kornzweig syndrome, metachromaticleukodystrophy (MLD), adrenoleukodystrophy, and nerve damage due topernicious anemia; viral infection such as progressive multifocalleukoencephalopathy (PML), Lyme disease, or tabes dorsalis due tountreated syphilis; toxic exposure due to chronic alcoholism (which is apossible cause of Marchiafava-Bignami disease), chemotherapy, orexposure to chemicals such as organophosphates; or dietary deficienciessuch as vitamin B12 deficiency, vitamin E deficiency, and copperdeficiency. Some demyelination disorders can have unknown or multiplecauses such as trigeminal neuralgia, Marchiafava-Bignami disease andBell's palsy. In addition, demyelination can contribute to neuropathicpain. Compounds of the invention are expected to be useful in treatingdemyelination disorders.

Since LPA is a proinflammatory factor reducing the amount of LPAproducted by inhibiting ATX is useful for treating inflammatorydisorders such as asthma, allergies, arthritis, inflammatoryneuropathies, transplantation rejection, Crohn's disease, ulcerativecolitis, lupus erythematosis, psoriasis, an inflammatory bowelcondition, and diabetes.

LPA has been shown to be involved in wound healing and stimulates theproliferation and migration of endothelial cells promoting processessuch as angiogenesis. However, these same processes when deregulated canpromote tumor growth and metastasis, and LPA is thought to contribute tothe development, progression, and metastasis of several types of cancerincluding ovarian, prostate, melanoma, breast, head and neck cancers(see Gendaszewska-Darmach, Acta Biochimica Polonica (2008),55(2):227-240). In addition, since ATX is located outside the cell incirculation, ATX inhibitors are expected to be of most benefit outsidethe cell. Therefore, ATX inhibitors are expected to be useful intreating cancer, particularly multidrug resistant (MDR) cancers wheredrug efflux mechanisms are the largest contributor to the drugresistance.

A compound of the invention, or a pharmaceutically acceptable saltthereof, formulated as a pharmaceutical composition and administered toa mammalian host, such as a human patient in a variety of forms adaptedto the chosen route of administration, e.g., orally or parenterally, aseyedrops, by intravenous, intramuscular, topical or subcutaneous routes.

Thus, compound of the invention, or a pharmaceutically acceptable saltthereof, may be systemically administered, e.g., orally, in combinationwith a pharmaceutically acceptable vehicle such as an inert diluent oran assimilable edible carrier. They may be enclosed in hard or softshell gelatin capsules, may be compressed into tablets, or may beincorporated directly with the food of the patient's diet. For oraltherapeutic administration, the active compound may be combined with oneor more excipients and used in the form of ingestible tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, or wafers, andthe like. Such compositions and preparations should contain at leastabout 0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositionscan be such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like can include thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; or a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl or propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscan contain a preservative to prevent the growth of microorganisms.

Exemplary pharmaceutical dosage forms for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, or nontoxicglyceryl esters, and mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, or thimerosal, and the like. In many cases, it will be preferableto include isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate or gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationcan be vacuum drying and the freeze drying techniques, which can yield apowder of the active ingredient plus any additional desired ingredientpresent in the previously sterile-filtered solutions.

For topical administration, a compound of the invention may be appliedin pure form, e.g., when they are liquids. However, it can be generallybe desirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Exemplary solid carriers can include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina and the like. Usefulliquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid ofnon-toxic surfactants. Adjuvants such as fragrances and additionalantimicrobial agents can be added to optimize the properties for a givenuse. The resultant liquid compositions can be applied from absorbentpads, used to impregnate bandages and other dressings, or sprayed ontothe affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts oresters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of the invention to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508), each of which is incorporated by reference inits entirety.

Useful dosages of the compounds of the invention can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949, which is incorporated by reference in its entirety.

Generally, the concentration of the compound(s) of the invention in aliquid composition, such as a lotion, can be from about 0.1 to about 25weight percent, preferably from about 0.5-10 weight percent. Theconcentration in a semi-solid or solid composition such as a gel or apowder can be about 0.1-5 wt-%, preferably about 0.5-2.5 weight percentbased on the total weight of the composition.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment can vary not only with the particular saltselected but also with the route of administration, the nature of thecondition being treated and the age and condition of the patient and canbe ultimately at the discretion of the attendant physician or clinician.In general, however, a dose can be in the range of from about 0.1 toabout 10 mg/kg of body weight per day.

The compound can be conveniently administered in unit dosage form; forexample, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredientper unit dosage form. In some embodiments, a dose of 5 mg/kg or less canbe suitable.

The active ingredient can be administered so as to achieve a desiredpeak plasma concentration of the active compound. The desired peakplasma concentration can be from about 0.5 μM to about 75 μM,preferably, about 1 μM to 50 μM, or about 2 μM to about 30 μM. This maybe achieved, for example, by the intravenous injection of a 0.05 to 5%solution of the active ingredient, optionally in saline, or orallyadministered as a bolus containing between about 1 mg to about 100 mg ofthe active ingredient.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four, or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The disclosed method can include a kit comprising a compound of theinvention and instructional material which can describe administeringthe compound or a composition comprising the compound to a cell or asubject. This should be construed to include other embodiments of kitsthat are known to those skilled in the art, such as a kit comprising a(preferably sterile) solvent for dissolving or suspending the compoundor composition prior to administering the compound or composition to acell or a subject. Preferably, the subject can be a human.

In accordance with the disclosed methods, as described above or asdiscussed in the Examples below, there can be employed conventionalchemical, cellular, histochemical, biochemical, molecular biology,microbiology, and in vivo techniques which are known to those of skillin the art. Such techniques are explained fully in the literature.

EXAMPLES

In one embodiment, certain compounds of the invention, andpharmaceutically acceptable salts thereof, may be prepared according togeneral scheme 1:

In one embodiment, certain compounds of the invention, andpharmaceutically acceptable salts thereof, may be prepared according togeneral scheme 2:

In one embodiment, certain compounds of the invention, andpharmaceutically acceptable salts thereof, may be prepared according togeneral scheme 3:

Example 1 4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid Step 1:4-(((6-hydroxynaphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate

6-hydroxy-2-naphthaldehyde (520 mg, 3.02 mmol, 1.0 eq) and methyl4-aminobicyclo[2.2.2]octane-1-carboxylate (663 mg, 3.62 mmol, 1.2 eq)were dissolved in toluene (100 mL). Magnesium sulfate (72 mg, 0.60 mmol,0.2 eq) was added to the solution and refluxed for 48 h. The solvent wasremoved in vacuo. The residue was dissolved in THF (150 mL) and sodiumcyanoborohydride (571 mg, 9.06 mmol, 3.0 eq) was added. The mixture wasrefluxed for 24 h. The solvent was removed in vacuo. Water (50 mL) wasadded to the residue and extracted with EtOAc (2×150 mL). The combinedorganic phase was washed with brine and dried over Na₂SO₄. The organicphase was concentrated to give methyl4-(((6-hydroxynaphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylateas yellow solid (819 mg, Y: 80%). ESI-MS (M+H)⁺: 340.2. ¹H NMR (400 MHz,DMSO-d₆) δ: 9.98 (s, 1H), 8.91 (br, 1H), 7.89 (s, 1H), 7.77 (d, J=9.2Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 1.6 Hz, 1H), 7.15 (s,1H), 7.14 (dd, J=8.0, 2.4 Hz, 1H), 4.17 (s, 2H), 3.60 (s, 3H), 1.91-1.87(m, 12H).

Step 2:4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

Methyl4-(((6-hydroxynaphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate(100 mg, 0.295 mmol, 1.0 eq), cyclohexyl methanesulfonate (100 mg, 0.885mmol, 3.0 eq) and sodium hydroxide (35 mg, 0.875 mmol, 3.0 eq) weredissolved in DMF (2 mL). The mixture was stirred at 100° C. for 2 h.After cooling to rt, 1 N HCl was added to adjust pH=6-7 and extractedwith DCM (2×40 mL). The organic phase was washed with brine and driedover Na₂SO₄. After filtration and concentration, the residue waspurified by prep-HPLC (65% MeOH/H₂O) to give4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid as a white solid (40 mg, yield: 33% in two steps). ESI-MS (M+H)⁺:408.2. ¹H NMR (400 MHz, CD₃OD) δ: 7.89 (s, 1H), 7.84 (d, J=8.4 Hz, 1H),7.81 (d, J=8.8 Hz, 1H), 7.49 (dd, J=8.8, 2.0 Hz, 1H), 7.28 (d, J=2.0 Hz,1H), 7.20 (dd, J=8.8, 2.4 Hz, 1H), 4.52-4.48 (m, 1H), 4.24 (s, 2H),2.04-1.99 (m, 14H), 1.86-1.83 (m, 2H), 1.63-1.47 (m, 6H).

Example 24-(((6-((trans-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 34 mg, white solid, yield: 27% in two steps. ESI-MS (M+H)⁺: 422.3.¹H NMR (400 MHz, CD₃OD) δ: 7.78 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.69(d, J=9.2 Hz, 1H), 7.37 (dd, J=8.4, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H),7.07 (dd, J=9.2, 2.4 Hz, 1H), 4.32-4.25 (m, 1H), 4.14 (s, 2H), 2.11-2.07(m, 2H), 1.94-1.88 (m, 12H), 1.74-1.71 (m, 2H), 1.41-1.39 (m, 3H),1.09-1.06 (m, 2H), 0.86 (d, J=6.8 Hz, 3H).

Example 34-(((6-((trans-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 36 mg, white solid, yield: 28% in two steps. ESI-MS (M+H)⁺: 436.2.¹H NMR (400 MHz, CD₃OD) δ: 7.89 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.80(d, J=9.2 Hz, 1H), 7.48 (dd, J=8.8, 2.0 Hz, 1H), 7.28 (d, J=2.8 Hz, 1H),7.18 (dd, J=8.8, 2.4 Hz, 1H), 4.43-4.39 (m, 1H), 4.26 (s, 2H), 2.25-2.21(m, 2H), 2.05-1.99 (m, 12H), 1.92-1.89 (m, 2H), 1.48-1.45 (m, 2H),1.33-1.28 (m, 3H), 1.19-1.13 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

Example 44-(((6-((trans-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 34 mg, white solid, yield: 26% in two steps. ESI-MS (M+H)⁺: 450.3.¹H NMR (400 MHz, CD₃OD) δ: 7.78 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.69(d, J=9.2 Hz, 1H), 7.37 (dd, J=8.4, 1.6 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H),7.07 (dd, J=8.8, 2.0 Hz, 1H), 4.30-4.25 (m, 1H), 4.14 (s, 2H), 2.16-2.13(m, 2H), 1.94-1.88 (m, 12H), 1.78-1.75 (m, 2H), 1.41-1.32 (m, 3H),1.19-1.09 (m, 3H), 0.83 (d, J=6.8 Hz, 6H).

Example 54-(((6-((trans-4-(tert-pentyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-(tert-pentyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid. 45 mg, white solid, yield: 32%in two steps. ESI-MS (M+H)⁺: 478.2. ¹H NMR (400 MHz, CD₃OD) δ: 7.78 (s,1H), 7.74 (d, J=8.4 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H), 7.38 (dd, J=8.8,1.6 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.06 (dd, J=8.8, 2.4 Hz, 1H),4.30-4.21 (m, 1H), 4.12 (s, 2H), 2.18-2.15 (m, 2H), 1.93-1.90 (m, 12H),1.76-1.73 (m, 2H), 1.32-1.14 (m, 8H), 0.76-0.72 (m, 8H).

Example 64-(((6-((trans-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 26 mg, white solid, yield: 18% in two steps. ESI-MS (M+H)⁺: 483.3.¹H NMR (400 MHz, CD₃OD) δ: 7.90 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.83(d, J=8.8 Hz, 1H), 7.50 (dd, J=8.8, 1.6 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H),7.29-7.26 (m, 4H), 7.22 (dd, J=9.2, 2.4 Hz, 1H), 7.20-7.17 (m, 1H),4.59-4.52 (m, 1H), 4.25 (s, 2H), 2.67-2.61 (m, 1H), 2.37-2.34 (m, 2H),2.05-1.98 (m, 14H), 1.78-1.71 (m, 2H), 1.69-1.63 (m, 2H).

Example 74-(((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 32 mg, white solid, yield: 25% in two steps. ESI-MS (M+H)⁺: 436.2.¹H NMR (400 MHz, CD₃OD) δ: 7.89 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.81(d, J=9.2 Hz, 1H), 7.48 (dd, J=8.4, 2.0 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H),7.21 (dd, J=8.8, 2.4 Hz, 1H), 4.51-4.49 (m, 1H), 4.26 (s, 2H), 2.05-1.94(m, 14H), 1.79-1.74 (m, 2H), 1.59-1.56 (m, 2H), 1.40-1.35 (m, 2H), 1.01(s, 3H), 1.00 (s, 3H).

Example 84-(((6-(spiro[2.5]octan-6-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-(spiro[2.5]octan-6-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 12 mg, white solid, yield: 25% in two steps. ESI-MS (M+H)⁺: 434.2.¹H NMR (400 MHz, CD₃OD) δ: 7.90 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.82(d, J=9.2 Hz, 1H), 7.49 (dd, J=8.8, 2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H),7.22 (dd, J=8.4, 2.0 Hz, 1H), 4.64-4.60 (m, 1H), 4.26 (s, 2H), 2.04-1.99(m, 14H), 1.83-1.74 (m, 2H), 1.60-1.54 (m, 2H), 1.43-1.39 (m, 2H),0.38-0.29 (m, 4H).

Example 94-(((6-(spiro[3.5]nonan-7-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-(spiro[3.5]nonan-7-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 46 mg, white solid, yield: 35% in two steps. ESI-MS (M+H)⁺: 448.3.¹H NMR (400 MHz, CD₃OD) δ: 7.89 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.81(d, J=9.2 Hz, 1H), 7.48 (dd, J=8.8, 2.0 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H),7.19 (dd, J=8.8, 2.4 Hz, 1H), 4.51-4.43 (m, 1H), 4.26 (s, 2H), 2.05-1.99(m, 12H), 1.94-1.81 (m, 10H), 1.55-1.52 (m, 4H).

Example 104-(((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 45 mg, white solid, yield: 33% in two steps. ESI-MS (M+H)⁺: 462.3.¹H NMR (400 MHz, CD₃OD) δ: 7.89 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.81(d, J=8.8 Hz, 1H), 7.48 (dd, J=8.4, 1.6 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H),7.20 (dd, J=8.8, 2.4 Hz, 1H), 4.53-4.51 (m, 1H), 4.25 (s, 2H), 2.05-1.99(m, 14H), 1.73-1.65 (m, 8H), 1.54-1.42 (m, 6H).

Example 114-(((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 50 mg, white solid, yield: 40% in two steps. ESI-MS (M+H)⁺: 476.3.¹H NMR (400 MHz, CD₃OD) δ: 7.89 (s, 1H), 7.86-7.79 (m, 2H), 7.48 (dd,J=8.4, 1.2 Hz, 1H), 7.28 (d, J=1.2 Hz, 1H), 7.20 (dd, J=8.8, 1.2 Hz,1H), 4.52-4.48 (m, 1H), 4.26 (s, 2H), 2.05-1.92 (m, 14H), 1.75-1.66 (m,4H), 1.47 (br, 8H), 1.37-1.30 (m, 4H).

Example 124-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid Step 1: methyl4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate

To a solution of methyl4-(((6-hydroxynaphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate(153 mg, 0.45 mmol, 1.0 eq) in DMF (3 mL) was added 1-bromoheptane (119mg, 0.68 mmol, 1.5 eq) and K₂CO₃ (124 mg, 0.9 mmol, 2.0 eq). The mixturewas stirred at 90° C. for 16 h. After cooling down to room temperature,the mixture was diluted with brine (50 mL) and extracted with EtOAc (60mL×3). The combined organic phase was dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by pre-HPLC to givemethyl4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylateas a white solid (120 mg, yield: 61%). ESI-MS (M+H)⁺: 321.1. ESI-MS(M+H)⁺: 438.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (s, 1H), 7.66 (d, J=9.2Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.4, 2.0 Hz, 1H), 7.13 (dd,J=8.8, 2.4 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 3.98 (t, J=6.8 Hz, 2H), 3.85(d, J=2.4 Hz, 2H), 3.60 (s, 3H), 1.83-1.80 (m, 2H), 1.50-1.30 (m, 20H),0.90 (t, J=7.2 Hz, 3H).

Step 2:4-((16-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

To a solution of methyl 4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate (120 mg, 0.27 mmol, 1.0 eq) inMeOH/THF/H₂O (2:2:1, 10 mL) was added NaOH (43 mg, 1.08 mmol, 4.0 eq).The mixture was stirred at reflux for 1 h. After cooling down to roomtemperature, the mixture was adjusted to pH=6 with 1 N HCl and extractedwith DCM (30 mL×2). The combined organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified bypre-HPLC to give4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid as a white solid (94 mg, yield: 81%). ESI-MS (M+H)⁺: 424.2. ¹H NMR(400 MHz, CD₃OD) δ: 7.90 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.81 (d, J=8.8Hz, 1H), 7.49 (dd, J=8.4, 1.6 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H), 7.21 (dd,J=8.8, 2.4 Hz, 1H), 4.25 (s, 2H), 4.11 (t, J=6.4 Hz, 2H), 2.05-2.01 (m,12H), 1.87-1.83 (m, 2H), 1.55-1.50 (m, 2H), 1.42-1.33 (m, 6H), 0.93 (t,J=7.2 Hz, 3H).

Example 134-(((6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 64 mg, white solid, yield: 51% in two steps. ESI-MS (M+H)⁺: 422.3.¹H NMR (500 MHz, CD₃OD) δ: 7.91 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.83(d, J=9.5 Hz, 1H), 7.49 (dd, J=8.5, 2.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H),7.24 (dd, J=9.0, 2.5 Hz, 1H), 4.76-4.74 (m, 1H), 4.26 (s, 2H), 2.09-2.00(m, 14H), 1.72-1.68 (m, 2H), 1.57-1.54 (m, 3H), 1.46-1.43 (m, 2H), 0.98(d, J=6.5 Hz, 3H).

Example 144-(((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 45 mg, white solid, yield: 35% in two steps. ESI-MS (M+H)⁺: 436.2.¹H NMR (400 MHz, CD₃OD) δ: 7.89 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.82(d, J=9.2 Hz, 1H), 7.48 (dd, J=8.4, 1.6 Hz, 1H), 7.28 (d, J=1.6 Hz, 1H),7.23 (dd, J=8.8, 2.0 Hz, 1H), 4.77-4.73 (m, 1H), 4.25 (s, 2H), 2.10-1.99(m, 14H), 1.67-1.59 (m, 4H), 1.44-1.30 (m, 5H), 0.94 (t, J=7.2 Hz, 3H).

Example 154-(((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-carboxylicAcid

The preparation of4-(((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 30 mg, white solid, yield: 23% in two steps. ESI-MS (M+H)⁺: 450.3.¹H NMR (400 MHz, CD₃OD) δ: 7.78 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.71(d, J=9.2 Hz, 1H), 7.37 (dd, J=8.4, 1.6 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H),7.11 (dd, J=8.8, 2.4 Hz, 1H), 4.64-4.63 (m, 1H), 4.12 (s, 2H), 2.03-2.00(m, 2H), 1.93-1.87 (m, 12H), 1.52-1.38 (m, 7H), 1.12-1.05 (m, 1H), 0.82(d, J=6.8 Hz, 6H).

Example 164-(((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 20 mg, white solid, yield: 14% in two steps. ESI-MS (M+H)⁺: 476.3.¹H NMR (400 MHz, CD₃OD) δ: 7.80 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.73(d, J=9.2 Hz, 1H), 7.39 (dd, J=8.4, 2.4 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H),7.14 (dd, J=8.8, 2.4 Hz, 1H), 4.72-4.70 (m, 1H), 4.13 (s, 2H), 2.13-2.08(m, 3H), 1.93-1.88 (m, 12H), 1.67-1.65 (m, 6H).

Example 174-(((6-((cis-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((cis-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 24 mg, white solid, yield: 17% in two steps. ESI-MS (M+H)⁺: 484.3.¹H NMR (400 MHz, CD₃OD) δ: 7.91 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.84(d, J=9.2 Hz, 1H), 7.50 (dd, J=8.4, 1.2 Hz, 1H), 7.34-7.17 (m, 6H),7.16-7.14 (m, 1H), 4.86-4.84 (m, 1H), 4.23 (s, 2H), 2.79-2.51 (m, 1H),2.25-2.22 (m, 2H), 2.01-1.93 (m, 14H), 1.84-1.69 (m, 4H).

Example 184-(((6-((trans-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 42 mg, white solid, yield: 31% in two steps. ESI-MS (M+H)⁺: 476.3.¹H NMR (400 MHz, CD₃OD) δ: 7.91 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.84(d, J=8.8 Hz, 1H), 7.50 (dd, J=8.8, 1.6 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H),7.26 (dd, J=8.8, 2.4 Hz, 1H), 4.84-4.81 (m, 1H), 4.26 (s, 2H), 2.23-2.20(m, 3H), 2.05-1.99 (m, 12H), 1.79-1.72 (m, 6H).

Example 194-(((6-((cis-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((cis-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 37 mg, white solid, yield: 27% in two steps. ESI-MS (M+H)⁺: 464.3.¹H NMR (400 MHz, CD₃OD) δ: 7.90 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.82(d, J=8.8 Hz, 1H), 7.49 (dd, J=8.4, 2.0 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H),7.23 (dd, J=8.8, 2.4 Hz, 1H), 4.76-4.74 (m, 1H), 4.22 (s, 2H), 2.19-2.16(m, 2H), 2.04-1.98 (m, 12H), 1.63-1.50 (m, 6H), 1.18-1.13 (m, 1H), 0.92(s, 9H).

Example 204-(((6-(cyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid Step 1: Methyl4-(((6-hydroxyquinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate

A mixture of 6-((tert-butyldimethylsilyl)oxy)quinoline-2-carbaldehyde (1g, 3.48 mmol) and methyl 4-amino bicyclo[2.2.2]octane-1-carboxylatehydrochloride salt (766 mg, 4.18 mmol, 1.2 eq) in dry toluene (200 mL)was stirred at reflux for 48 h. Then the mixture was concentrated andthe residue was dissolved in THF (150 mL), and NaBH₃CN (658 mg, 10.44mmol, 3 eq) was added. The reaction mixture was stirred at reflux for 16h. After concentration, EA (200 mL) was added and the mixture was washedwith H₂O (100 mL×2). The organic phase was dried and concentrated togive methyl4-(((6-((tert-butyldimethylsilyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylateas yellow solid (crude 1.5 g), which was used for the next step withoutfurther purification. ESI-MS (M+H)⁺: 455.2.

To a solution of crude methyl4-(((6-((tert-butyldimethylsilyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate(1.5 g, 3.3 mmol) in MeOH (100 mL) was added conc. HCl (5.5 mL, 12 M, 20eq) slowly at 0° C. Then the reaction mixture was stirred at roomtemperature for 4 h. The mixture was adjusted to pH=8 with sat. NaHCO₃and concentrated. The residue was extracted with EA (200 mL) and washedwith H₂O (200 mL×2). The organic phase was dried and concentrated togive methyl4-(((6-hydroxyquinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylateas yellow solid (940 mg, yield: 80% in two steps). ESI-MS (M+H)⁺: 341.2.¹H NMR (400 MHz, CDCl₃) δ: 7.65 (d, J=9.2 Hz, 1H), 7.30 (d, J=8.4 Hz,1H), 7.07 (dd, J=8.8, 2.4 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.37 (d,J=2.4 Hz, 1H), 3.93 (s, 2H), 3.66 (s, 3H), 1.96-1.92 (m, 6H), 1.83-1.79(m, 6H).

Step 2:4-(((6-(cyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-(cyclohexyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 40 mg, a yellow solid, yield: 37%. ESI-MS (M+H)⁺: 409.2, HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=8.4 Hz, 1H), 8.00 (d, J=9.2Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.43 (dd, J=9.2, 2.4 Hz, 1H), 7.31 (d,J=2.4 Hz, 1H), 4.54-4.52 (m, 1H), 4.47 (s, 2H), 2.09-2.03 (m, 14H),1.86-1.83 (m, 2H), 1.65-1.46 (m, 6H).

Example 214-(((6-((trans-4-methylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-methylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 34 mg, a white solid, yield: 27%. ESI-MS (M+H)⁺: 423.3, HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=8.4 Hz, 1H), 8.00 (d, J=9.2Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.40 (dd, J=9.2, 2.8 Hz, 1H), 7.31 (d,J=2.4 Hz, 1H), 4.47 (s, 2H), 4.44-4.40 (m, 1H), 2.22-2.20 (m, 2H),2.04-2.00 (m, 12H), 1.84-1.81 (m, 2H), 1.50-1.44 (m, 3H), 1.20-1.17 (m,2H), 0.96 (d, J=6.4 Hz, 3H).

Example 224-(((6-((trans-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 50 mg, a yellow solid, yield: 36%. ESI-MS (M+H)⁺: 437.2, HPLC:98.93%. ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=8.4 Hz, 1H), 8.00 (d,J=9.2 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.41 (dd, J=9.2, 2.4 Hz, 1H),7.32 (d, J=2.4 Hz, 1H), 4.47 (s, 2H), 4.45-4.40 (m, 1H), 2.25-2.22 (m,2H), 2.06-2.00 (m, 12H), 1.93-1.90 (m, 2H), 1.53-1.49 (m, 2H), 1.35-1.27(m, 3H), 1.20-1.10 (m, 2H), 0.95 (t, J=7.2 Hz, 3H).

Example 234-(((6-((trans-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 34 mg, a white solid, yield: 25%. ESI-MS (M+H)⁺: 451.2, HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 8.27 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.40 (dd, J=8.8, 2.8 Hz, 1H), 7.32 (d,J=2.8 Hz, 1H), 4.47 (s, 2H), 4.42-4.38 (m, 1H), 2.27-2.25 (m, 2H),2.04-2.00 (m, 12H), 1.88-1.85 (m, 2H), 1.50-1.43 (m, 3H), 1.29-1.23 (m,3H), 0.93 (d, J=6.4 Hz, 6H).

Example 244-(((6-((trans-4-(tert-pentyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-(tert-pentyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 24 mg, a yellow solid, yield: 16%. ESI-MS (M+H)⁺: 479.3, HPLC:97.56%. ¹H NMR (400 MHz, CD₃OD) δ: 8.25 (d, J=8.4 Hz, 1H), 7.98 (d,J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.39 (dd, J=8.8, 2.4 Hz, 1H),7.31 (d, J=2.8 Hz, 1H), 4.46 (s, 2H), 4.41-4.35 (m, 1H), 2.30-2.27 (m,2H), 2.02-1.97 (m, 12H), 1.87-1.84 (m, 2H), 1.47-1.41 (m, 2H), 1.38-1.22(m, 5H), 0.88-0.81 (m, 9H).

Example 254-(((6-((trans-4-phenylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-phenylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 40 mg, a yellow solid, yield: 12%. ESI-MS (M+H)⁺: 485.2, HPLC:95.88%. ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=8.4 Hz, 1H), 8.01 (d,J=9.2 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.43 (dd, J=8.8, 2.4 Hz, 1H),7.37 (d, J=2.8 Hz, 1H), 7.30-7.24 (m, 4H), 7.19-7.14 (m, 1H), 4.58-4.51(m, 1H), 4.38 (s, 2H), 2.63-2.56 (m, 1H), 2.35-2.32 (m, 2H), 1.98-1.93(m, 14H), 1.78-1.57 (m, 4H).

Example 264-(((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 50 mg, a yellow solid, yield: 42%. ESI-MS (M+H)⁺: 437.3, HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 8.21 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.43 (dd, J=9.2, 2.8 Hz, 1H), 7.32 (d,J=2.4 Hz, 1H), 4.53-4.50 (m, 1H), 4.47 (s, 2H), 2.03-1.95 (m, 14H),1.78-1.75 (m, 2H), 1.60-1.55 (m, 2H), 1.42-1.37 (m, 2H), 1.00 (s, 3H),0.97 (s, 3H).

Example 274-(((6-(spiro[2.5]octan-6-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-(spiro[2.5]octan-6-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 20 mg, a white solid, yield: 30%. ESI-MS (M+H)⁺: 435.0, HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=8.8 Hz, 1H), 8.00 (d, J=9.6Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.45 (dd, J=9.2, 2.0 Hz, 1H), 7.35 (d,J=2.0 Hz, 1H), 4.65-4.61 (m, 1H), 4.47 (s, 2H), 2.04-2.01 (m, 14H),1.83-1.75 (m, 2H), 1.60-1.55 (m, 2H), 1.43-1.39 (m, 2H), 0.37-0.30 (m,4H).

Example 284-(((6-(spiro[3.5]nonan-7-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-(spiro[3.5]nonan-7-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 80 mg, a yellow solid, yield: 43%. ESI-MS (M+H)⁺: 449.2, HPLC:99.68%. ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=8.8 Hz, 1H), 8.00 (d,J=8.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.42 (dd, J=8.8, 2.8 Hz, 1H),7.35 (d, J=2.8 Hz, 1H), 4.51-4.49 (m, 1H), 4.47 (s, 2H), 2.03-2.01 (m,12H), 1.98-1.80 (m, 10H), 1.65-1.50 (m, 4H).

Example 294-(((6-(spiro[4.5]decan-8-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-(spiro[4.5]decan-8-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 44 mg, a white solid, yield: 32%. ESI-MS (M+H)⁺: 463.2, HPLC:100.00%. ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=8.4 Hz, 1H), 8.00 (d,J=9.2 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.8, 2.4 Hz, 1H),7.32 (d, J=2.4 Hz, 1H), 4.57-4.51 (m, 1H), 4.47 (s, 2H), 2.04-2.02 (m,14H), 1.65-1.72 (m, 8H), 1.46-1.54 (m, 6H).

Example 304-(((6-(spiro[5.5]undecan-3-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-(spiro[5.5]undecan-3-yloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 60 mg, a yellow solid, yield: 43%. ESI-MS (M+H)⁺: 477.3, HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 8.25 (d, J=8.4 Hz, 1H), 8.00 (d, J=9.2Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.8, 2.4 Hz, 1H), 7.31 (d,J=2.8 Hz, 1H), 4.54-4.31 (m, 1H), 4.47 (s, 2H), 2.02-1.92 (m, 14H),1.77-1.68 (m, 4H), 1.50-1.46 (m, 8H), 1.38-1.30 (m, 4H).

Example 314-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylateStep 1: methyl4-(((6-(heptyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate

The preparation of methyl4-(((6-(heptyloxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylatewas the same as that of methyl4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate.60 mg, a yellow solid, yield: 52%. ESI-MS (M+H)⁺: 439.3. ¹H NMR (400MHz, CDCl₃) δ: 8.08 (d, J=8.4 Hz, 1H), 7.90 (d, J=9.6 Hz, 1H), 7.41 (dd,J=9.2, 2.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 4.52(s, 2H), 4.06 (t, J=6.8 Hz, 2H), 3.66 (s, 3H), 1.98-1.94 (m, 12H),1.88-1.83 (m, 2H), 1.52-1.48 (m, 2H), 1.41-1.31 (m, 6H), 0.91 (t, J=6.8Hz, 3H).

Step 2:4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate

The preparation of4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylatewas the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 35 mg, a yellow solid, yield: 60%. ESI-MS (M+H)⁺: 425.3, HPLC:95.53%. ¹H NMR (400 MHz, CD₃OD) δ: 8.27 (d, J=8.4 Hz, 1H), 8.00 (d,J=9.2 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.44 (dd, J=9.2, 2.8 Hz, 1H),7.30 (d, J=2.8 Hz, 1H), 4.48 (s, 2H), 4.13 (t, J=6.4 Hz, 2H), 2.04-1.98(m, 12H), 1.88-1.83 (m, 2H), 1.56-1.50 (m, 2H), 1.44-1.33 (m, 6H), 0.93(t, J=6.8 Hz, 3H).

Example 324-(((6-((cis-4-methylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((cis-4-methylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 50 mg, a yellow solid, yield: 30%. ESI-MS (M+H)⁺: 423.3, HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 8.23 (d, J=8.4 Hz, 1H), 8.00 (d, J=9.2Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.45 (dd, J=9.6, 2.8 Hz, 1H), 7.31 (d,J=2.4 Hz, 1H), 4.77-4.73 (m, 1H), 4.42 (s, 2H), 2.09-1.97 (m, 14H),1.69-1.64 (m, 2H), 1.57-1.53 (m, 3H), 1.45-1.41 (m, 2H), 0.96 (d, J=6.0Hz, 3H).

Example 334-(((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 10 mg, a yellow solid, yield: 8%. ESI-MS (M+H)⁺: 436.9, HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 8.24 (d, J=8.4 Hz, 1H), 8.01 (d, J=9.2Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.45 (dd, J=9.2, 2.8 Hz, 1H), 7.31 (d,J=2.4 Hz, 1H), 4.77-4.75 (m, 1H), 4.40 (s, 2H), 2.11-2.06 (m, 2H),2.01-1.99 (m, 12H), 1.72-1.60 (m, 4H), 1.47-1.39 (m, 2H), 1.34-1.30 (m,3H), 0.95 (t, J=6.8 Hz, 3H).

Example 344-(((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 35 mg, a yellow solid, yield: 60%. ESI-MS (M+H)⁺: 451.3, HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 8.24 (d, J=8.8 Hz, 1H), 8.01 (d, J=9.2Hz, 1H), 7.47-7.44 (m, 2H), 7.31 (d, J=2.8 Hz, 1H), 4.78-4.76 (m, 1H),4.46 (s, 2H), 2.15-2.11 (m, 2H), 2.03-1.98 (m, 12H), 1.69-1.46 (m, 7H),1.25-1.17 (m, 1H), 0.93 (d, J=6.8 Hz, 6H).

Example 354-(((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 70 mg, a yellow solid, yield: 60%. ESI-MS (M+H)⁺: 477.2, HPLC:100%. ¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=8.8 Hz, 1H), 8.03 (d, J=9.2Hz, 1H), 7.50-7.47 (m, 2H), 7.35 (d, J=2.8 Hz, 1H), 4.86-4.83 (m, 1H),4.48 (s, 2H), 2.28-2.20 (m, 3H), 2.04-2.00 (m, 12H), 1.81-1.71 (m, 6H).

Example 364-(((6-((cis-4-phenylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((cis-4-phenylcyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 50 mg, a yellow solid, yield: 30%. ESI-MS (M+H)⁺: 485.2, HPLC:97.27%. ¹H NMR (400 MHz, CD₃OD) δ: 8.23 (d, J=8.8 Hz, 1H), 8.02 (d,J=9.2 Hz, 1H), 7.52 (dd, J=9.2, 2.8 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H),7.36 (d, J=2.4 Hz, 1H), 7.30-7.25 (m, 4H), 7.18-7.16 (m, 1H), 4.86-4.84(m, 1H), 4.34 (s, 2H), 2.69-2.63 (m, 1H), 2.26-2.23 (m, 2H), 1.99-1.79(m, 16H), 1.73-1.70 (m, 2H).

Example 374-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid Step 1:cis-4-tert-Butylcyclohexyl methanesulfonate

Cis-4-t-butylcyclohexanol (6.0 g, 38.5 mmol, 1.0 eq.) was dissolved indichloromethane (10 mL). Then methanesulfonic anhydride (8.03 g, 46.2mmol, 1.1 eq.) was added to the mixture slowly at 0° C. Thentriethylamine (6.4 mL, 46.2 mmol, 1.5 eq.) was added to the mixture andthe mixture stirred at room temperature for 3 h. The mixture wasextracted with dichloromethane and the organic layer was concentrated togive product as a white power (8.0 g, yield: 90%). The product was usedto next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ4.99-4.98 (m, 1H), 3.02 (s, 3H), 2.14-2.12 (m, 2H), 1.65-1.28 (m, 7H),0.84 (s, 9H).

Step 2: 2-Bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene

6-bromonaphthalen-2-ol (CAS no. 15231-91-1) (3.0 g, 14.8 mmol, 1.0 eq.)was dissolved in a mixture of t-butanol/2-butanone (4 mL/2 mL). Thencesium carbonate (12 g, 37.2 mmol, 2.5 eq.) was added to the mixture andthe mixture was stirred at 110° C. for 10 min. Thentrans-4-tert-butylcyclohexyl methanesulfonate (3.48 g, 16.2 mmol, 1.1eq.) was added to the mixture. The suspension was stirred at 110° C.under a nitrogen atmosphere for 15 h. The reaction mixture was extractedwith ethyl acetate and the organic layer was purified by silica gelcolumn chromatography using petroleum ether as eluent to give2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene as a slightyellow solid (1.7 g, yield: 32%). ESI-MS: 361.0 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.89 (s, 1H), 7.63 (d, 1H), 7.56 (d, 1H), 7.47 (d, 1H),7.15-7.11 (m, 2H), 4.26-4.24 (m, 1H), 2.27-2.25 (m, 2H), 1.89-1.87 (m,2H), 1.45-1.09 (m, 5H), 0.89 (s, 9H).

Step 3: 6-(trans-4-tert-Butylcyclohexyloxy)-2-naphthaldehyde

2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (2.249 g, 6.25mmol, 1.0 eq.) was dissolved in THF (10 mL) under nitrogen atmosphere.Then the mixture was cooled down to −78° C. and a solution of n-BuLi inTHF (2.5 M, 7.5 mL, 18.8 mmol, 3.0 eq.) was added to the mixturedropwise. The mixture was stirred at −78° C. for 15 min. Then DMF (2.4mL, 31.2 mmol, 5.0 eq.) was added to the mixture and stirred at −78° C.for 1 h. When the reaction completed, 1 M HCl was added to adjust the pHto 6. The mixture was extracted with EtOAc and the organic layer wasconcentrated and purified by silica gel chromatography using petroleumether/ethyl acetate (10/1) as eluent to give6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde as a white solid(1.16 g, 60%). EDI-MS: 311.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.08 (s,1H), 8.24 (s, 1H), 7.92-7.87 (m, 2H), 7.77 (d, 1H), 7.22-7.19 (m, 2H),4.42-4.30 (m, 1H), 2.30-2.28 (m, 2H), 1.93-1.90 (m, 2H), 1.48-1.11 (m,5H), 0.82 (s, 9H).

Step 4: 6-Bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-iodonaphthalene

A solution of 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene

(160.0 g, 444.4 mmol) in methylene chloride (2.5 L) was purged under anatmosphere of argon. N-iodosuccinimide (202.1 g, 888.8 mmol) andzirconium tetrachloride (20.4 g, 88.9 mmol) was added and the reactionwas stirred at room temperature under an atmosphere of argon. Thereaction was monitored by ¹H NMR and showed complete conversion toproduct after 30 minutes. The mixture was then concentrated underreduced pressure to give ˜250 g crude as a brown solid. The crudematerial was purified by silica gel chromatography with hexanes to give200 g of desired product as a brown solid (yield: 92.6%). EDI-MS: 487.1(M+H)+.

Step 5:6-Bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene

A solution of6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-iodonaphthalene

(210.0 g, 433 mmol), hexamethylphosphoramide (386.4 g, 2.16 mol; 5 eq)in N,N-dimethylformamide (2.0 L) was degassed by stirring under vacuumand replacing the vacuum with argon (4 times). To this mixture was addedcopper(I) iodide (140.0 g, 735 mmol; 1.7 eq) and methylfluorosulphonyldifluoroacetate (415 g, 2.16 mol; 5 eq). The reactionmixture was warmed to 80° C. under an atmosphere of argon. Afterstirring for 6 hrs, thin layer chromatography showed complete conversionto product. Saturated NaHCO₃ solution was added to adjust the final pHto 9-10 followed by adding EtOAc (3.5 L). The mixture was extracted withEtOAc (2.5 L×3), and washed with brine (1.0 L×4), then dried over Na₂SO₄(500 g). The solvent was removed under reduced pressure to give crude195 g as a sticky off white solid with purity of >90%, which waspurified by silica gel chromatography with 0-30% EtOAc in hexanes togive the final product (156 g, yield: 84.3%). EDI-MS: 430.0 (M+H)⁺.

Step 6:6-(trans-4-tert-Butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde

To a solution of6-bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene(1 g, 2.3 mmol) in THF (30 mL) was added n-BuLi (2.8 mL, 2.5M in THF,3.0 equiv) dropwise at −78° C. in 30 min, then DMF (840 mg, 11.5 mmol,5.0 equiv) was added slowly at −78° C. The reaction mixture was stirredat −78° C. for 1.5 h. Then saturated NH₄Cl solution was added to themixture to quench the reaction. The mixture was extracted with EtOAc andpurified by silica gel chromatography (petroleum ether:ethyl acetate10:1) to give product6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehydeas a yellow solid (608 mg, yield: 70%). ESI-MS: 379.2 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ: 10.13 (s, 1H), 8.28 (d, 2H), 8.08 (d, 1H), 7.98-8.01(dd, 1H), 7.41 (d, 1H), 4.39 (m, 1H), 2.21 (d, 2H), 1.90 (d, 2H),1.49-1.58 (q, 2H), 1.10-1.17 (m, 3H), 0.86 (s, 9H)

Step 7: ethyl4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate

The preparation of ethyl4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylatewas similar to that of methyl4-(((6-hydroxynaphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate. yellow solid, 60 mg, Y: 35%. ESI-MS(M+H)⁺: 560.3. ¹H NMR (400 MHz, CDCl₃) δ: 8.12 (d, J=8.0 Hz, 1H), 7.88(d, J=9.2 Hz, 1H), 7.83 (s, 1H), 7.54 (d, J=9.2 Hz, 1H), 7.24 (d, J=9.2Hz, 1H), 4.28-4.20 (m, 1H), 4.07 (q, J=6.8 Hz, 2H), 3.84 (s, 2H),2.14-2.12 (m, 2H), 1.86-1.84 (m, 2H), 1.75-1.70 (m, 12H), 1.24-1.02 (m,8H), 0.87 (s, 9H).

Step 8:4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid, as a white solid, 35mg, Y: 60%. ESI-MS (M+H)⁺: 532.3. HPLC: 100.00%; ¹H NMR (400 MHz, CD₃OD)δ: 8.22 (d, J=8.0 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.98 (s, 1H), 7.60(d, J=9.2 Hz, 1H), 7.55-7.52 (m, 1H), 4.50-4.42 (m, 1H), 4.27 (s, 2H),2.22-2.19 (m, 2H), 2.05-1.98 (m, 12H), 1.92-1.89 (m, 2H), 1.53-1.46 (m,2H), 1.23-1.11 (m, 3H), 0.90 (s, 9H).

Example 384-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid Step 1: 6-((trans-4-(tert-butyl)cyclohexyl)oxy)-2-methylquinoline

A mixture of 2-methylquinolin-6-ol (2 g, 12.6 mmol, 1 eq),cis-4-tert-butylcyclohexyl methanesulfonate (4.42 g, 18.9 mmol, 1.5 eq)and NaOH (1.06 g, 25.2 mmol, 2 eq) in DMF (6 mL) was stirred at 80° C.for 16 h. Then H₂O (15 mL) was added to the reaction mixture which wasextracted with EA (30 mL×2). The collected organic layer was dried(Na₂SO₄) and concentrated. The crude product was purified by silica gelchromatography (PE:EA=20:1) to give6-((trans-4-(tert-butyl)cyclohexyl)oxy)-2-methylquinoline as a yellowsolid, 1.6 g, Y: 42%. ESI-MS (M+H)⁺: 298.3. ¹H NMR (400 MHz, CDCl₃) δ:7.91 (d, J=8.4 Hz, 2H), 7.32 (dd, J=9.2, 2.8 Hz, 1H), 7.22 (d, J=8.4 Hz,1H), 7.06 (d, J=2.8 Hz, 1H), 4.27-4.22 (m, 1H), 2.27 (s, 3H), 2.28-2.25(m, 2H), 1.91-1.88 (m, 2H), 1.49-1.43 (m, 2H), 1.19-1.10 (m, 3H), 0.86(s, 9H).

Step 2: 6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-iodo-2-methylquinoline

The preparation of6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-iodo-2-methylquinoline was thesame as that of6-Bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-iodonaphthalene, 1.35 g,as a yellow solid, Y: 55%. ESI-MS (M+H)⁺: 424.1. ¹H NMR (400 MHz, CDCl₃)δ: 8.30 (d, J=9.2 Hz, 1H), 7.95 (d, J=9.2 Hz, 1H), 7.38 (d, J=9.2 Hz,1H), 7.27 (d, J=8.4 Hz, 1H), 4.32-4.25 (m, 1H), 2.73 (s, 3H), 2.25-2.22(m, 2H), 1.88-1.85 (m, 2H), 1.64-1.58 (m, 2H), 1.11-1.09 (m, 3H), 0.86(s, 9H).

Step 3:6-((trans-4-(tert-butyl)cyclohexyl)oxy)-2-methyl-5-(trifluoromethyl)quinoline

The preparation of6-((trans-4-(tert-butyl)cyclohexyl)oxy)-2-methyl-5-(trifluoromethyl)quinolonewas the same as that of6-Bromo-2-(trans-4-tert-butylcyclohexyloxy)-1-(trifluoromethyl)naphthalene,550 mg, as a yellow solid, Y: 43%. ESI-MS (M+H)⁺: 366.3. ¹H NMR (400MHz, CDCl₃) δ: 8.43 (d, J=8.8 Hz, 1H), 8.14 (d, J=9.6 Hz, 1H), 7.51 (d,J=9.2 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 4.35-4.30 (m, 1H), 2.72 (s, 3H),2.21-1.98 (m, 2H), 1.89-1.87 (m, 2H), 1.58-1.49 (m, 2H), 1.15-1.11 (m,3H), 0.88 (s, 9H).

Step 4:6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)quinoline-2carbaldehyde

A mixture of6-((trans-4-(tert-butyl)cyclohexyl)oxy)-2-methyl-5-(trifluoromethyl)quinoline(550 mg, 1.51 mmol, 1 eq) and SeO₂ (670 mg, 6.04 mmol, 4 eq) in toluene(8 mL) was refluxed for 16 h. After cooling down to room temperature,the mixture was filtered and the filtrate was concentrated. The crudeproduct was purified by silica gel column to give6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)quinoline-2-carbaldehyde(PE:EA=20:1) as a yellow solid, 320 mg, Y: 52%, ESI-MS (M+H)⁺: 380.2. ¹HNMR (400 MHz, CDCl₃) δ: 10.17 (s, 1H), 8.68 (d, J=8.8 Hz, 1H), 8.34 (d,J=9.2 Hz, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.64 (d, J=9.6 Hz, 1H), 4.48-4.41(m, 1H), 2.25-2.21 (m, 2H), 1.93-1.90 (m, 2H), 1.62-1.54 (m, 2H),1.18-1.11 (m, 3H), 0.89 (s, 9H).

Step 5: methyl4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate

The preparation of methyl4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylatewas the same as that of methyl4-(((6-hydroxynaphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate, 20 mg, as a yellow solid, Y: 8%.ESI-MS (M+H)⁺: 547.3.

Step 6:4-(((6-((trans-4-(tert-buty)cyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

The preparation of4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid was the same as that of4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid, 10 mg, as a yellow solid, Y: 51%. ESI-MS (M+H)⁺: 533.3, HPLC:92.11%. ¹H NMR (400 MHz, CD₃OD) δ: 8.50 (d, J=8.4 Hz, 1H), 8.19 (d,J=9.6 Hz, 1H), 7.73 (d, J=9.6 Hz, 1H), 7.49 (d, J=9.6 Hz, 1H), 4.47-4.44(m, 1H), 4.42 (s, 2H), 2.13-2.11 (m, 2H), 1.93 (br, 10H), 1.83-1.80 (m,2H), 1.45-1.38 (m, 2H), 1.23-1.10 (m, 4H), 1.05-0.97 (m, 1H), 0.81 (s,9H).

Example 392-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine

A mixture of 6-((trans-4-(tert-butyl)cyclohexyl)oxy)-2-naphthaldehyde(100 mg, 0.32 mmol, 1.0 eq), 2-(piperidin-4-yl)pyridine (62 mg, 0.38mmol, 1.2 eq) and NaBH(OAc)₃ (136 mg, 0.64 mol, 2.0 eq) in DCE (20 mL)was stirred at room temperature for 2 h. Water (20 mL) was added to themixture. The organic layer was washed with brine (20 mL), dried overNa₂SO₄ and concentrated to give2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridineas a white solid (72 mg, Y: 49%). ESI-MS (M+H)⁺: 457.0, HPLC: 100.00%.¹H NMR (400 MHz, CD₃OD) δ: 8.58 (d, J=4.8 Hz, 1H), 8.01 (t, J=8.4 Hz,1H), 7.96 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.83 (d, J=9.2 Hz, 1H),7.56-7.46 (m, 3H), 7.31 (d, J=2.0 Hz, 1H), 7.19 (dd, J=8.8, 2.0 Hz, 1H),4.49 (s, 2H), 4.41-4.35 (m, 1H), 3.69-3.66 (m, 2H), 3.26-3.17 (m, 3H),2.29-2.10 (m, 6H), 1.92-1.89 (m, 2H), 1.44-1.41 (m, 2H), 1.31-1.25 (m,2H), 1.15-1.11 (m, 1H), 0.92 (s, 9H).

Example 402-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyrimidine

The preparation of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyrimidinewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.8.8 mg, as yellow oil, Y: 18%. ESI-MS (M+H)⁺: 458.2, HPLC: 100.00%. ¹HNMR (400 MHz, CD₃OD) δ: 8.75 (d, J=8.4 Hz, 2H), 7.94 (s, 1H), 7.88 (d,J=8.8 Hz, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.36 (t,J=4.8 Hz, 1H), 7.31 (s, 1H), 7.19 (dd, J=8.8, 2.0 Hz, 1H), 4.46 (s, 2H),4.41-4.35 (m, 1H), 3.61-3.59 (m, 2H), 3.32-3.24 (m, 3H), 2.29-2.18 (m,6H), 1.94-1.91 (m, 2H), 1.45-1.42 (m, 2H), 1.39-1.26 (m, 2H), 1.16-1.13(m, 1H), 0.89 (s, 9H).

Example 411-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-phenylpiperazine

The preparation of1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-phenylpiperazinewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.64 mg, as a yellow solid, Y: 35%. ESI-MS (M+H)⁺: 457.0, HPLC: 100.00%.¹H NMR (400 MHz, CD₃OD) δ: 7.77 (t, J=9.2 Hz, 2H), 7.71 (s, 1H), 7.44(dd, J=8.8, 1.2 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H),7.18 (d, J=8.0 Hz, 1H), 7.11 (dd, J=8.8, 2.4 Hz, 1H), 6.91 (d, J=8.0 Hz,2H), 6.76 (t, J=8.0 Hz, 1H), 4.40-4.35 (m, 1H), 3.63 (s, 2H), 3.14-3.12(m, 4H), 2.55-2.53 (m, 4H), 2.22-2.19 (m, 2H), 2.01-1.83 (m, 2H),1.33-1.02 (m, 5H), 0.88 (s, 9H).

Example 421-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-3-yl)piperazine

The preparation of1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-3-yl)piperazinewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.30 mg, as a yellow solid, Y: 41%. ESI-MS (M+H)⁺: 458.0, HPLC: 100.00%.¹H NMR (400 MHz, CD₃OD) δ: 8.38 (d, J=2.8 Hz, 1H), 8.13 (d, J=5.2 Hz,1H), 8.01 (dd, J=8.8, 2.4 Hz, 1H), 7.86 (s, 1H), 7.78 (d, J=8.4 Hz, 1H),7.76 (dd, J=8.4, 2.4 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.4,2.0 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.09 (dd, J=8.8, 2.0 Hz, 1H), 4.45(s, 2H), 4.31-4.25 (m, 1H), 3.64-3.62 (m, 4H), 3.43-3.40 (m, 4H),2.19-2.16 (m, 2H), 1.83-1.80 (m, 2H), 1.37-1.28 (m, 2H), 1.22-1.16 (m,2H), 1.06-1.02 (m, 1H), 0.82 (s, 9H).

Example 431-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)-1,4-diazepane

The preparation of1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-pyridin-2-yl)-1,4-diazepanewas the same as that of2-(1-6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.93 mg, as a yellow solid, Y: 45%. ESI-MS (M+H)⁺: 472.2, HPLC: 100.00%.¹H NMR (400 MHz, CD₃OD) δ: 8.05 (d, J=5.2 Hz, 1H), 7.98 (d, J=8.8 Hz,1H), 7.94 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.81 (d, J=9.2 Hz, 1H), 7.53(dd, J=8.4, 1.6 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.23-7.19 (m, 2H), 6.99(t, J=6.8 Hz, 1H), 4.54 (s, 2H), 4.40-4.38 (m, 1H), 4.10-4.08 (m, 2H),3.76-3.73 (m, 2H), 3.57-3.54 (m, 3H), 2.43-2.40 (m, 2H), 2.30-2.27 (m,2H), 1.94-1.91 (m, 2H), 1.48-1.39 (m, 2H), 1.33-1.23 (m, 3H), 1.17-1.13(m, 1H), 0.93 (s, 9H).

Example 442-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrimidine

The preparation of2-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrimidinewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.85 mg, as a yellow solid, Y: 51%. ESI-MS (M+H)⁺: 459.3, HPLC: 100.00%.¹H NMR (400 MHz, CD₃OD) δ: 8.30 (d, J=4.8 Hz, 2H), 7.77-7.70 (m, 3H),7.42 (dd, J=8.8, 1.2 Hz, 1H), 7.17 (dd, J=8.8, 2.4 Hz, 1H), 7.14 (s,1H), 6.57 (t, J=4.8 Hz, 1H), 4.85-4.65 (m, 2H), 4.31 (s, 2H), 4.31-4.28(m, 1H), 3.80-2.80 (m, 6H), 2.28-2.25 (m, 2H), 1.90-1.88 (m, 2H),1.45-1.42 (m, 2H), 1.20-1.18 (m, 3H), 0.90 (s, 9H).

Example 452-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrazine

The preparation of2-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrazinewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.89 mg, as a yellow solid, Y: 51%. ESI-MS (M+H)⁺: 459.3, HPLC: 100.00%.¹H NMR (400 MHz, CD₃OD) δ: 8.32 (s, 1H), 8.18 (dd, J=2.4, 1.6 Hz, 1H),7.96 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.83 (d,J=8.8 Hz, 1H), 7.54 (dd, J=8.4, 1.6 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H),7.20 (dd, J=8.4, 2.0 Hz, 1H), 4.91-4.90 (m, 4H), 4.53 (s, 2H), 4.42-4.37(m, 1H), 3.50-3.48 (m, 4H), 2.30-2.27 (m, 2H), 1.94-1.91 (m, 2H),1.45-1.39 (m, 2H), 1.33-1.14 (m, 3H), 0.93 (s, 9H).

Example 461-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-4-yl)piperazine

The preparation of1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-4-yl)piperazinewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.44 mg, as a yellow solid, Y: 43%. ESI-MS (M+H)⁺: 458.0, HPLC: 100.00%.¹H NMR (400 MHz, DMSO-d₆) δ: 8.14 (s, 2H), 7.78 (d, J=8.4 Hz, 1H), 7.76(d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.34 (d, J=2.0Hz, 1H), 7.12 (dd, J=8.8, 2.0 Hz, 1H), 6.79 (d, J=5.2 Hz, 2H), 4.38-4.35(m, 1H), 3.62 (s, 2H), 3.18-3.16 (m, 4H), 2.51-2.49 (m, 4H), 2.21-2.19(m, 2H), 1.83-1.80 (m, 2H), 1.38-1.03 (m, 5H), 0.88 (s, 9H).

Example 471-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyrimidin-2-yl)-1,4-diazepane

The preparation of1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyrimidin-2-yl)-1,4-diazepanewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.90 mg, as a yellow solid, Y: 49%. ESI-MS (M+H)⁺: 473.4, HPLC: 98.35%. ¹HNMR (400 MHz, CD₃OD) δ: 8.05 (d, J=5.2 Hz, 2H), 7.89 (s, 1H), 7.82 (d,J=8.4 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.49 (dd, J=8.4, 1.6 Hz, 1H),7.25 (d, J=1.6 Hz, 1H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 6.69 (t, J=5.2 Hz,1H), 4.44 (s, 2H), 4.40-4.31 (m, 1H), 4.00-3.58 (m, 5H), 3.32-3.20 (m,3H), 2.25-2.22 (m, 4H), 1.87-1.83 (m, 2H), 1.39-1.36 (m, 2H), 1.22-1.19(m, 2H), 1.09-1.06 (m, 1H), 0.88 (s, 9H).

Example 484-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrimidine

The preparation of4-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)pyrimidinewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.9 mg, as yellow oil, Y: 11%. ESI-MS (M+H)⁺: 459.2, HPLC: 93.96%. ¹H NMR(400 MHz, CD₃OD) δ: 8.58 (s, 1H), 8.18-8.17 (m, 1H), 7.80 (s, 1H), 7.75(d, J=8.4 Hz, 1H), 7.70 (d, J=9.2 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.19(d, J=2.0 Hz, 1H), 7.07 (dd, J=8.8, 2.4 Hz, 1H), 6.97 (d, J=6.8 Hz, 1H),4.30-4.25 (m, 3H), 4.03-4.00 (m, 4H), 3.21-3.19 (m, 4H), 2.19-2.16 (m,2H), 1.83-1.80 (m, 2H), 1.34-1.02 (m, 5H), 0.82 (s, 9H).

Example 494-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)-2-methylpyrimidine

The preparation of4-(4-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperazin-1-yl)-2-methylpyrimidinewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.30 mg, as a yellow solid, Y: 37%. ESI-MS (M+H)⁺: 473.0, HPLC: 98.76%. ¹HNMR (400 MHz, CD₃OD) δ: 8.11 (d, J=7.2 Hz, 1H), 7.81 (s, 1H), 7.75 (d,J=8.4 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H), 7.42 (dd, J=8.4, 1.6 Hz, 1H),7.19 (d, J=2.4 Hz, 1H), 7.07 (dd, J=8.8, 2.4 Hz, 1H), 6.97 (d, J=7.6 Hz,1H), 4.33 (s, 2H), 4.29-4.23 (m, 1H), 4.10-4.06 (m, 4H), 3.28-3.26 (m,4H), 2.49 (s, 3H), 2.18-2.15 (m, 2H), 1.82-1.79 (m, 2H), 1.36-1.01 (m,5H), 0.81 (s, 9H).

Example 501-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-phenylpiperidine

The preparation of1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-phenylpiperidinewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.34 mg, as a white solid, Y: 22%. ESI-MS (M+H)⁺: 456.3, HPLC: 97.45%. ¹HNMR (400 MHz, CD₃OD) δ: 7.96 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.84 (d,J=9.2 Hz, 1H), 7.55 (dd, J=8.4, 1.6 Hz, 1H), 7.33-7.30 (m, 3H),7.26-7.19 (m, 4H), 4.48 (s, 2H), 4.42-4.36 (m, 1H), 3.66-3.62 (m, 2H),3.24-3.17 (m, 2H), 2.93-2.86 (m, 1H), 2.30-2.26 (m, 2H), 2.12-2.07 (m,2H), 2.03-1.91 (m, 4H), 1.47-1.40 (m, 2H), 1.33-1.23 (m, 2H), 1.17-1.10(m, 1H), 0.93 (s, 9H).

Example 511-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine

The preparation of1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazinewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine,200 mg, as a white solid, Y: 55%. ESI-MS (M+H)⁺: 458.2. HPLC: 97.89%. ¹HNMR (400 MHz, CDCl₃) δ: 8.19 (dd, J=5.2, 1.2 Hz, 1H), 7.76 (t, J=8.4 Hz,2H), 7.71 (s, 1H), 7.52-7.48 (m, 1H), 7.44 (dd, J=8.4, 1.2 Hz, 1H), 7.34(d, J=2.8 Hz, 1H), 7.11 (dd, J=8.8, 2.0 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H),6.62 (dd, J=6.8, 4.8 Hz, 1H), 4.37-4.34 (m, 1H), 3.62 (s, 2H), 3.49-3.46(m, 4H), 2.51-2.48 (m, 4H), 2.22-2.19 (m, 2H), 1.83-1.79 (m, 2H),1.33-1.07 (m, 5H), 0.88 (s, 9H).

Example 521-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazineStep 1: 2-bromo-6-((cis-4-isopropylcyclohexyl)oxy)naphthalene

To a mixture of 6-bromonaphthalen-2-ol (1.39 g, 6.25 mmol, 1.0 eq),trans-4-isopropyl cyclohexanol (1.33 g, 9.38 mmol, 1.5 eq) and PPh₃(3.28 g, 12.5 mmol, 2.0 eq) in dry THF (30 mL) was quickly added DIAD(2.53 g, 12.5 mmol, 2.0 eq) in one portion at 0° C. under N₂. Then thereaction mixture was stirred at room temperature for 2 h. The solventwas removed in vacuum and the residue was purified by silica gel columnwith PE as eluent to give2-bromo-6-((cis-4-isopropylcyclohexyl)oxy)naphthalene as a white solid(1.18 g, Y: 55%). ESI-MS (M+H)⁺: 347.1. ¹H NMR (400 MHz, CDCl₃) δ: 7.83(d, J=1.2 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.40(dd, J=8.8, 2.0 Hz, 1H), 7.11 (dd, J=8.8, 2.0 Hz, 1H), 7.04 (d, J=2.4Hz, 1H), 4.60-4.58 (m, 1H), 2.06-2.03 (m, 2H), 1.54-1.36 (m, 7H),1.10-1.04 (m, 1H), 0.83 (d, J=6.8 Hz, 6H).

Step 2: 6-((cis-4-isopropylcyclohexyl)oxy)-2-naphthaldehyde

2-bromo-6-((cis-4-isopropylcyclohexyl)oxy)naphthalene (1.18 g, 3.4 mmol,1.0 eq) was dissolved in dry THF (20 mL) and cooled to −78° C. under N₂.n-BuLi (6.4 mL, 1.6 M, 3.0 eq) was added to the solution. The mixturewas stirred at −78° C. for 15 min and DMF (1.2 mL, 17.0 mmol, 5.0 eq)was added. The mixture was stirred at −78° C. for 1 h and then washedwith water (20 mL) and extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with brine (20 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel column chromatography (PE/EA=40/1) to give6-((cis-4-isopropylcyclohexyl)oxy)-2-naphthaldehyde as a yellow solid(657 mg, Y: 66%). ESI-MS (M+H)⁺: 297.2. ¹H NMR (400 MHz, CDCl₃) δ: 10.08(s, 1H), 8.23 (s, 1H), 7.90-7.87 (m, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.25(dd, J=9.2, 2.8 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 4.74-4.72 (m, 1H),2.16-2.12 (m, 2H), 1.66-1.46 (m, 7H), 1.19-1.14 (m, 1H), 0.90 (d, J=6.8Hz, 6H).

Step 3:1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine

A mixture of 6-((cis-4-isopropylcyclohexyl)oxy)-2-naphthaldehyde (107mg, 0.36 mmol, 1.0 eq) and 1-(pyridin-2-yl)piperazine (70 mg, 0.432mmol, 1.2 eq) in DCE (15 mL) was stirred at reflux for 2 h. Aftercooling down to room temperature, NaBH(OAc)₃ (153 mg, 0.72 mmol, 2.0 eq)was added to the mixture and stirred at room temperature for 4 h. Water(15 mL) was added to the mixture and the mixture was extracted with DCM(20 mL×2). The combined organic phase was washed with water (15 mL) andbrine (20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by pre-HPLC to give1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine.77 mg, as white gum, Y: 66%. ESI-MS (M+H)⁺: 444.3, HPLC: 100.00%. ¹H NMR(400 MHz, CD₃OD) δ: 8.00 (dd, J=5.6, 0.8 Hz, 1H), 7.84 (s, 1H),7.80-7.70 (m, 3H), 7.42 (dd, J=8.0, 1.2 Hz, 1H), 7.17 (s, 1H), 7.13-7.07(m, 2H), 6.85 (t, J=6.8 Hz, 1H), 4.63-4.61 (m, 1H), 4.41 (s, 2H),3.82-3.80 (m, 4H), 3.36-3.34 (m, 4H), 2.01-1.97 (m, 2H), 1.53-1.33 (m,7H), 1.07-1.05 (m, 1H), 0.79 (d, J=6.8 Hz, 6H).

Example 531-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazineStep 1: 6-((cis-4-ethylcyclohexyl)oxy)-2-naphthaldehyde

The preparation of 6-((cis-4-ethylcyclohexyl)oxy)-2-naphthaldehyde wasthe same as that of 6-((cis-4-isopropylcyclohexyl)oxy)-2-naphthaldehyde.440 mg, as a yellow solid, Y: 74%. ESI-MS (M+H)⁺: 283.2. ¹H NMR (400MHz, CDCl₃) δ: 10.08 (s, 1H), 8.24 (s, 1H), 7.91-7.88 (m, 2H), 7.76 (d,J=8.4 Hz, 1H), 7.25 (dd, J=8.4, 2.4 Hz, 1H), 7.19 (d, J=2.8 Hz, 1H),4.73-4.70 (m, 1H), 2.11-2.07 (m, 2H), 1.67-1.57 (m, 4H), 1.47-1.37 (m,2H), 1.33-1.26 (m, 3H), 0.91 (t, J=7.2 Hz, 3H).

Step 2:1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine

The preparation of1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazinewas the same as that of1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine.90 mg, as a yellow solid, Y: 46%. ESI-MS (M+H)⁺: 430.3, HPLC: 99.53%. ¹HNMR (400 MHz, CD₃OD) δ: 8.16 (d, J=3.6 Hz, 1H), 7.95 (s, 1H), 7.89-7.83(m, 2H), 7.63 (t, J=8.8 Hz, 1H), 7.53 (dd, J=8.4, 1.6 Hz, 1H), 7.31 (d,J=2.0 Hz, 1H), 7.25 (dd, J=8.8, 2.0 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H),6.80 (dd, J=6.8, 1.6 Hz, 1H), 4.92-4.90 (m, 4H), 4.78-4.76 (m, 1H), 4.48(s, 2H), 3.40-3.36 (m, 4H), 2.10-2.06 (m, 2H), 1.71-1.60 (m, 4H),1.47-1.30 (m, 5H), 0.94 (t, J=7.2 Hz, 3H).

Example 541-(pyridin-2-yl)-4-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)piperazineStep 1: 2-bromo-6-(spiro[4.5]decan-8-yloxy)naphthalene

The preparation of 2-bromo-6-(spiro[4.5]decan-8-yloxy)naphthalene wasthe same as that of2-bromo-6-((cis-4-isopropylcyclohexyl)oxy)naphthalene. 1.09 g, as awhite solid, Y: 76%. ESI-MS (M+H)⁺: 359.1.

Step 2: 6-(spiro[4.5]decan-8-yloxy)-2-naphthaldehyde

The preparation of 6-(spiro[4.5]decan-8-yloxy)-2-naphthaldehyde was thesame as that of 6-((cis-4-isopropylcyclohexyl)oxy)-2-naphthaldehyde. 700mg, as a yellow solid, Y: 76%. ESI-MS (M+H)⁺: 309.2. ¹H NMR (400 MHz,CDCl₃) δ: 10.08 (s, 1H), 8.24 (s, 1H), 7.91-7.88 (m, 2H), 7.77 (d, J=8.8Hz, 1H), 7.22 (dd, J=8.8, 2.4 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 4.50-4.44(m, 1H), 2.02-1.97 (m, 2H), 1.73-1.58 (m, 8H), 1.51-1.38 (m, 6H).

Step 3:1-(pyridin-2-yl)-4-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)piperazine

The preparation of1-(pyridin-2-yl)-4-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)piperazinewas the same as that of1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine.144 mg, as a white solid, Y: 65%. ESI-MS (M+H)⁺: 456.3, HPLC: 100.00%.¹H NMR (400 MHz, CD₃OD) δ: 8.02 (d, J=4.4 Hz, 1H), 7.83 (s, 1H), 7.75(d, J=8.4 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.63 (t, J=8.4 Hz, 1H), 7.42(dd, J=8.4, 1.2 Hz, 1H), 7.17 (s, 1H), 7.09 (dd, J=8.8, 2.4 Hz, 1H),6.92 (d, J=8.8 Hz, 1H), 6.75 (t, J=6.8 Hz, 1H), 4.39-4.37 (m, 3H),3.75-3.73 (m, 4H), 3.31-3.29 (m, 4H), 1.87-1.84 (m, 2H), 1.59-1.51 (m,8H), 1.38-1.27 (m, 6H).

Example 551-((6-(heptyloxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine Step1: 2-bromo-6-(heptyloxy)naphthalene

The preparation of 2-bromo-6-(heptyloxy)naphthalene was the same as thatof 2-bromo-6-((cis-4-isopropylcyclohexyl)oxy)naphthalene. 1.2 g, as ayellow solid, Y: 52%. ESI-MS (M+H)⁺: 321.1. ¹H NMR (400 MHz, CDCl₃) δ:7.88 (d, J=2.0 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H),7.46 (dd, J=8.8, 2.0 Hz, 1H), 7.14 (dd, J=8.8, 2.4 Hz, 1H), 7.05 (d,J=2.8 Hz, 1H), 4.02 (t, J=6.8 Hz, 2H), 1.85-1.79 (m, 2H), 1.51-1.44 (m,2H), 1.40-1.24 (m, 6H), 0.90 (t, J=6.8 Hz, 3H).

Step 2: 6-(heptyloxy)-2-naphthaldehyde

The preparation of 6-(heptyloxy)-2-naphthaldehyde was the same as thatof 6-((cis-4-isopropylcyclohexyl)oxy)-2-naphthaldehyde. 516 mg, as ayellow solid, Y: 51%. ESI-MS (M+H)⁺: 270.1.

Step 3:1-((6-(heptyloxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine

The preparation of1-((6-(heptyloxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine wasthe same as that of1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine.29 mg, as a yellow solid, Y: 39%. ESI-MS (M+H)⁺: 418.2, HPLC: 100.00%.¹H NMR (400 MHz, CD₃OD) δ: 8.12 (d, J=3.6 Hz, 1H), 7.91 (s, 1H), 7.84(d, J=8.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.60 (td, J=8.0, 2.0 Hz, 1H),7.51 (d, J=8.0 Hz, 1H), 7.22 (s, 1H), 7.19 (dd, J=8.8, 2.0 Hz, 1H), 6.86(d, J=8.4 Hz, 1H), 6.75 (dd, J=6.8, 5.2 Hz, 1H), 5.00-4.96 (m, 2H), 4.41(s, 2H), 4.03 (t, J=6.4 Hz, 2H), 3.79-3.77 (m, 2H), 3.32-3.30 (m, 4H),1.82-1.75 (m, 2H), 1.50-1.30 (m, 8H), 0.90 (t, J=6.8 Hz, 3H).

Example 566-((cis-4-isopropylcyclohexyl)oxy)-2-((4-(pyridin-2-yl)piperazin-1-yl)methyl)quinolineStep 1: 6-((cis-4-isopropylcyclohexyl)oxy)-2-methylquinoline

To a mixture of 2-methylquinolin-6-ol (2.0 g, 12.6 mmol, 1.0 eq),trans-4-isopropyl cyclohexanol (1.96 g, 13.8 mmol, 1.1 eq) and PPh₃(3.96 g, 15.1 mmol, 1.2 eq) in dry toluene (60 mL) was quickly addedDIAD (3.05 g, 15.1 mmol, 1.2 eq) in one portion at 0° C. under N₂. Thenthe reaction mixture was stirred at room temperature for 24 h. Thesolvent was removed in vacuum and the residue was purified by silica gelcolumn (PE:EA=10:1) to give6-((cis-4-isopropylcyclohexyl)oxy)-2-methylquinoline as yellow oil (2.43g, Y: 65%). ESI-MS (M+H)⁺: 284.1. ¹H NMR (400 MHz, CDCl₃) δ: 7.91 (d,J=9.2 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.35 (dd, J=9.2, 2.8 Hz, 1H),7.21 (d, J=8.0 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 4.66-4.64 (m, 1H), 2.70(s, 3H), 2.14-2.10 (m, 2H), 1.57-1.47 (m, 7H), 1.26-1.23 (m, 1H),0.91-085 (m, 6H).

Step 2: 6-((cis-4-isopropylcyclohexyl)oxy)quinoline-2-carbaldehyde

To a solution of 6-((cis-4-isopropylcyclohexyl)oxy)-2-methylquinoline(2.34 g, 8.27 mmol, 1.0 eq) in dry toluene (100 mL) was added SeO₂ (3.67g, 33.1 mmol, 4.0 eq). The reaction mixture was heated to reflux withstirring for 6 h. After cooling to room temperature and filtration, thefiltrate was concentrated in vacuo. The residue was purified by silicagel column (PE/EA=10:1) to give6-((cis-4-isopropylcyclohexyl)oxy)quinoline-2-carbaldehyde as a paleyellow solid (1.5 g, Y: 63%). ESI-MS (M+H)⁺: 298.1. ¹H NMR (400 MHz,CDCl₃) δ: 10.19 (s, 1H), 8.15-8.13 (m, 2H), 7.98 (d, J=8.4 Hz, 1H), 7.50(dd, J=9.2, 2.8 Hz, 1H), 7.13 (d, J=2.8 Hz, 1H), 4.75-4.73 (m, 1H),2.17-2.13 (m, 2H), 1.66-1.47 (m, 7H), 1.18-1.16 (m, 1H), 0.91 (d, J=6.8Hz, 6H).

Step 36-((cis-4-isopropylcyclohexyl)oxy)-2-((4-(pyridin-2-yl)piperazin-1-yl)methyl)quinoline

The preparation of6-((cis-4-isopropylcyclohexyl)oxy)-2-((4-(pyridin-2-yl)piperazin-1-yl)methyl)quinolinewas the same as that of1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine.135 mg, as pale yellow gum, Y: 75%. ESI-MS (M+H)⁺: 445.3, HPLC:99.31%-99.36%. ¹H NMR (400 MHz, CD₃OD) δ: 8.41 (d, J=8.4 Hz, 1H), 8.13(dd, J=5.6, 1.6 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.86-7.85 (m, 1H), 7.60(d, J=8.4 Hz, 1H), 7.54 (dd, J=9.2, 2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H),7.18 (d, J=9.2 Hz, 1H), 6.95-6.92 (m, 1H), 4.82-4.80 (m, 1H), 4.62 (s,2H), 3.97-3.94 (m, 4H), 3.49-3.47 (m, 4H), 2.17-2.13 (m, 2H), 1.67-1.68(m, 7H), 1.24-1.20 (m, 1H), 0.93 (d, J=6.8 Hz, 6H).

Example 573-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid Step 1: methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azet)meth)azetidin-3-yl)cyclohexanecarboxylate

To a mixture of 6-((cis-4-isopropylcyclohexyl)oxy)-2-naphthaldehyde (160mg, 0.54 mmol, 1.0 eq) and 3-(azetidin-3-yl)cyclohexanecarboxylic acidhydrochloride (142 mg, 0.648 mmol, 1.2 eq) in MeOH (10 mL) was added TEA(55 mg, 0.54 mmol, 1.0 eq). The mixture was stirred at room temperaturefor 2 h. Then NaBH₃CN (68 mg, 1.08 mmol, 2.0 eq) was added and stirredat room temperature for 16 h. After concentration, the residue waspurified by pre-HPLC to give methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylateas a white solid (180 mg, Y: 70%). ESI-MS (M+H)⁺: 478.4.

Step 2:3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid

To a solution of methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate(180 mg, 0.38 mmol, 1.0 eq) in MeOH (10 mL) was added NaOH (61 mg, 1.52mmol, 4.0 eq) in H₂O (1 mL). The reaction solution was heated to 65° C.for 4 h with stirring. After cooling down to rt, 1 N HCl was added toadjust pH=6. Then the solvent was evaporated in vacuo to give yellowsolid, which was purified by pre-HPLC to give3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid. 77 mg, as a white solid, Y: 44%. ESI-MS (M+H)⁺:464.3, HPLC: 100.00%. ¹H NMR (400 MHz, CD₃OD) δ: 7.90 (s, 1H), 7.84 (d,J=8.8 Hz, 2H), 7.45 (d, J=8.4 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.24 (dd,J=8.8, 2.4 Hz, 1H), 4.76-4.75 (m, 1H), 4.52-4.43 (m, 2H), 4.23-3.96 (m,4H), 2.68-2.58 (m, 1H), 2.36-2.28 (m, 1H), 2.14-2.11 (m, 2H), 2.01-1.85(m, 3H), 1.68-1.45 (m, 9H), 1.37-1.30 (m, 2H), 1.24-1.17 (m, 1H),1.03-0.78 (m, 8H).

Example 583-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid Step 1: methyl3-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate

The preparation of methyl3-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylatewas the same as that of methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate.80 mg, as a yellow solid, Y: 45%. ESI-MS (M+H)⁺: 492.3.

Step 2:3-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid

The preparation of3-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid was the same as that of3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid. 40 mg, as a white solid, Y: 60%. ESI-MS (M+H)⁺:478.3, HPLC: 100.00%. ¹H NMR (400 MHz, CDCl₃) δ: 7.75-7.67 (m, 3H), 7.47(dd, J=8.4, 16 Hz, 1H), 7.16-7.12 (m, 2H), 4.30-4.23 (m, 1H), 4.17 (s,2H), 3.97-3.88 (m, 4H), 3.61-3.48 (m, 2H), 2.56-2.52 (m, 1H), 2.27-2.20(m, 3H), 2.03-1.75 (m, 4H), 1.52-1.37 (m, 5H), 1.28-1.05 (m, 5H), 0.89(s, 9H).

Example 593-(1-((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid Step 1: methyl3-(1-((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate

The preparation of methyl3-(1-((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylatewas the same as that of methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate.78 mg, as yellow gum, Y: 37%. ESI-MS (M+H)⁺: 465.3. ¹H NMR (400 MHz,CDCl₃) δ: 8.23 (d, J=8.4 Hz, 1H), 8.09 (d, J=9.2 Hz, 1H), 7.88 (d, J=8.4Hz, 1H), 7.47 (dd, J=9.2, 2.8 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 4.62 (s,2H), 4.45-4.42 (m, 1H), 4.23-4.21 (m, 2H), 4.01-3.99 (m, 2H), 3.65 (s,3H), 2.66-2.64 (m, 1H), 2.37-2.35 (m, 1H), 1.98-1.92 (m, 3H), 1.86-1.75(m, 4H), 1.58-1.54 (m, 3H), 1.36-1.28 (m, 6H), 1.00 (s, 3H), 0.99 (s,3H), 0.88-0.85 (m, 1H).

Step 2:3-(1-((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid

The preparation of3-(1-((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid was the same as that of3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid. 36 mg, as yellow gum, Y: 54%. ESI-MS (M+H)⁺: 451.2,HPLC: 96.10%-98.29%. ¹H NMR (400 MHz, CD₃OD) δ: 8.24 (d, J=8.4 Hz, 1H),7.98 (d, J=9.6 Hz, 1H), 7.43-7.39 (m, 2H), 7.30 (d, J=2.4 Hz, 1H), 4.72(s, 2H), 4.54-4.49 (m, 1H), 4.39-4.38 (m, 2H), 4.10-4.08 (m, 2H),2.78-2.70 (m, 1H), 2.35-2.32 (m, 1H), 1.98-1.94 (m, 5H), 1.78-1.72 (m,7H), 1.41-1.36 (m, 4H), 1.01 (s, 3H), 1.00 (s, 3H), 0.88-0.86 (m, 1H).

Example 603-(1-((6-(heptyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid Step 1: methyl3-(1-((6-(heptyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate

The preparation of methyl3-(1-((6-(heptyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylatewas the same as that of methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate.1.2 g, as a yellow solid, Y: 28%. ESI-MS (M+H)⁺: 452.3.

Step 2:3-(1-((6-(heptyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid

The preparation of3-(1-((6-(heptyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid was the same as that of3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid. 22 mg, as a yellow solid, Y: 40%. ESI-MS (M+H)⁺:438.0, HPLC: 100.00%. ¹H NMR (400 MHz, CD₃OD) δ: 7.91 (s, 1H), 7.85 (d,J=8.4 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 1.2 Hz, 1H),7.25 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.8, 2.0 Hz, 1H), 4.93 (s, 2H),4.16-4.08 (m, 4H), 4.00-3.96 (m, 2H), 2.64-2.59 (m, 1H), 2.26-2.24 (m,1H), 2.00-1.84 (m, 5H), 1.65-1.52 (m, 4H), 1.50-1.28 (m, 8H), 1.01-0.90(m, 5H).

Example 613-(1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid Step 1: methyl3-(1-((6-((-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate

The preparation of methyl3-(1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylatewas the same as that of methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate.100 mg, as a white solid, Y: 68%. ESI-MS (M+H)⁺: 464.3.

Step 2:3-(1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid

The preparation of3-(1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid was the same as that of3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid. 40 mg, as a white solid, Y: 50%. ESI-MS (M+H)⁺:450.2, HPLC: 98.19%. ¹H NMR (400 MHz, CD₃OD) δ: 7.90 (s, 1H), 7.83 (d,J=8.8 Hz, 2H), 7.45 (dd, J=8.4, 1.6 Hz, 1H), 7.28 (s, 1H), 7.22 (d,J=9.2 Hz, 1H), 4.76-4.73 (m, 1H), 4.43 (br, 2H), 4.14-4.08 (m, 2H),4.04-3.95 (m, 2H), 2.65-2.61 (m, 1H), 2.35-2.30 (m, 2H), 2.08-1.84 (m,5H), 1.69-1.58 (m, 6H), 1.46-1.30 (m, 7H), 0.96-0.79 (m, 4H).

Example 623-(1-((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid Step 1: methyl3-(1-((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate

The preparation of methyl3-(1-((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate was the same as that of methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate.110 mg, as a white solid, Y: 67%. ESI-MS (M+H)⁺: 464.3.

Step 2:3-(1-((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid

The preparation of3-(1-((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid was the same as that of3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid. 78 mg, as a white solid, Y: 74%. ESI-MS (M+H)⁺:450.3, HPLC: 100.00%. ¹H NMR (400 MHz, CD₃OD) δ: 7.78 (s, 1H), 7.72 (d,J=8.0 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.15 (d,J=2.0 Hz, 1H), 7.09 (dd, J=8.8, 2.4 Hz, 1H), 4.39-4.29 (m, 3H),4.08-3.97 (m, 2H), 3.90-3.84 (m, 2H), 2.55-2.46 (m, 1H), 2.21-2.15 (m,1H), 1.88-1.71 (m, 5H), 1.66-1.41 (m, 6H), 1.27-1.16 (m, 4H), 0.88-0.66(m, 8H).

Example 633-(1-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid Step 1: methyl3-(1-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate

The preparation of methyl3-(1-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylatewas the same as that of methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate.160 mg, as a white solid, Y: 60%. ESI-MS (M+H)⁺: 490.3.

Step 2:3-(1-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid

The preparation of3-(1-((6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid was the same as that of3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid. 113 mg, as a white solid, Y: 60%. ESI-MS (M+H)⁺:446.2, HPLC: 100.00%. ¹H NMR (400 MHz, CD₃OD) δ: 7.90 (s, 1H), 7.85 (d,J=8.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.29 (d,J=2.0 Hz, 1H), 7.20 (dd, J=9.2, 2.4 Hz, 1H), 4.55-4.50 (m, 2H),4.43-4.41 (m, 1H), 4.22-3.97 (m, 4H), 2.68-2.58 (m, 1H), 2.33-2.28 (m,1H), 2.01-1.84 (m, 5H), 1.73-1.61 (m, 10H), 1.56-1.41 (m, 6H), 1.37-1.28(m, 2H), 1.02-0.80 (m, 2H).

Example 643-(1-((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid Step 1: methyl3-(1-((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate

The preparation of methyl3-(1-((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylatewas the same as that of methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate.150 mg, as pale yellow gum, Y: 39%. ESI-MS (M+H)⁺: 465.2. ¹H NMR (400MHz, CDCl₃) δ: 7.97 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.42 (d,J=8.8 Hz, 1H), 7.36 (dd, J=9.2, 2.8 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H),4.66-4.64 (m, 1H), 3.88 (s, 2H), 3.65 (s, 3H), 3.68-3.52 (m, 2H),2.98-2.96 (m, 2H), 2.15-2.11 (m, 2H), 2.09-2.05 (m, 2H), 1.90-1.79 (m,3H), 1.64-1.55 (m, 5H), 1.44-1.41 (m, 3H), 1.32-1.25 (m, 7H), 0.90 (t,J=7.6 Hz, 3H).

Step 2:3-(1-((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid

The preparation o3-(1-((6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid was the same as that of3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid. 35 mg, as pale yellow gum, Y: 30%. ESI-MS (M+H)⁺:451.2, HPLC: 94.16%-98.14%. ¹H NMR (400 MHz, CD₃OD) δ: 8.24 (d, J=8.8Hz, 1H), 7.99 (d, J=9.2 Hz, 1H), 7.44 (dd, J=8.8, 2.4 Hz, 1H), 7.41 (d,J=8.8 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 4.76-4.72 (m, 3H), 4.39-4.37 (m,2H), 4.12-4.10 (m, 2H), 2.76-2.73 (m, 1H), 2.42-4.40 (m, 1H), 2.10-1.86(m, 5H), 1.71-1.63 (m, 6H), 1.43-1.29 (m, 7H), 1.03-0.95 (m, 1H), 0.92(t, J=7.2 Hz, 3H), 0.87-0.83 (m, 1H).

Example 653-(1-((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid Step 1: methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate

To a mixture of methyl6-((cis-4-isopropylcyclohexyl)oxy)quinoline-2-carbaldehyde (200 mg,0.673 mmol, 1.0 eq) and methyl 3-(azetidin-3-yl)cyclohexanecarboxylate(132 mg, 0.673 mmol, 1.0 eq) in DCM (40 mL) was added NaBH(OAc)₃ (285mg, 1.346 mmol, 2.0 eq). The mixture was stirred for 4 h at roomtemperature. Then saturated aqueous NaHCO₃ was added to adjust pH=8 andextracted with EtOAc (50 mL×2). The combined organic phase was washedwith water (15 mL) and brine (20 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EA) to give methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate as yellow gum (41 mg, Y: 13%). ESI-MS (M+H)⁺: 479.3.

Step 2:3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid

To the solution of methyl3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylate (35 mg, 0.073 mmol, 1.0 eq) in MeOH (20 mL) was added NaOH(58 mg, 1.46 mmol, 20.0 eq) in H₂O (4 ml). The reaction solution washeated to 80° C. for 16 h with stirring. After concentration, theresidue was adjusted to pH=6 with 1N HCl, extracted with EtOAc (50mL×2), washed with H₂O (15 mL) and brine (20 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified bypre-HPLC to give3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylic acid as colorless gum (5 mg, Y: 15%). ESI-MS (M+H)⁺:465.2,HPLC: 95.96%-97.07%. ¹H NMR (400 MHz, CD₃OD) δ: 8.11 (d, J=8.4 Hz, 1H),7.86 (d, J=9.2 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.34 (dd, J=9.2, 2.8 Hz,1H), 7.19 (d, J=2.8 Hz, 1H), 4.68-4.67 (m, 1H), 4.06 (s, 2H), 3.75-3.71(m, 2H), 3.34-3.30 (m, 2H), 2.06-2.02 (m, 3H), 1.82-1.72 (m, 3H),1.56-1.41 (m, 9H), 1.25-1.20 (m, 6H), 0.84 (d, J=6.8 Hz, 6H).

Example 664-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid

The preparation of4-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid was the same as that of1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)-4-(pyridin-2-yl)piperazine.85 mg, as a white solid, Y: 63%. ESI-MS (M+H)⁺: 478.3, HPLC: 100.00%. ¹HNMR (400 MHz, CD₃OD) δ: 7.89 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.81 (d,J=9.2 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.28 (d, J=1.6 Hz, 1H), 7.18 (dd,J=9.2, 2.0 Hz, 1H), 4.50-4.44 (m, 2H), 4.39-4.35 (m, 1H), 4.17-4.08 (m,2H), 4.00-3.93 (m, 2H), 2.75-2.55 (m, 2H), 2.28-2.25 (m, 2H), 2.02-1.99(m, 2H), 1.92-1.89 (m, 2H), 1.73-1.71 (m, 1H), 1.68-1.62 (m, 3H),1.60-1.52 (m, 3H), 1.33-1.21 (m, 3H), 1.18-1.09 (m, 2H), 0.92 (s, 9H).

Example 676-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane

The preparation of6-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptanewas the same as that of2-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)piperidin-4-yl)pyridine.50 mg, as a yellow solid, Y: 54%. ESI-MS (M+H)⁺: 492.3, HPLC: 100.00%.¹H NMR (400 MHz, CD₃OD) δ: 7.72 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.4 Hz,1H), 7.64 (s, 1H), 7.33 (dd, J=8.4, 1.6 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H),7.09 (dd, J=8.8, 2.4 Hz, 1H), 4.73 (s, 4H), 4.35-4.30 (m, 1H), 3.72 (s,2H), 3.51 (s, 4H), 2.28-2.25 (m, 2H), 1.92-1.87 (m, 2H), 1.45-1.36 (m,2H), 1.30-1.20 (m, 2H), 1.15-1.08 (m, 1H), 0.91 (s, 9H).

Example 683-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid Step 1: ethyl3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.1]hexane-6-carboxylate

The preparation of ethyl3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylatewas the same as that of methyl4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate,86 mg, as a yellow solid, Y: 30%. ESI-MS (M+H)⁺: 450.3. ¹H NMR (400 MHz,CDCl₃) δ: 7.75 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.0 Hz, 1H),7.18-7.13 (m, 2H), 4.31-4.24 (m, 3H), 4.12 (q, J=7.2 Hz, 2H), 3.79-3.72(m, 2H), 3.28-3.25 (m, 2H), 2.41-2.39 (m, 1H), 2.24-2.19 (m, 4H),1.91-1.88 (m, 2H), 1.48-1.37 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 1.17-1.02(m, 3H), 0.90 (s, 9H).

Step 2:3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid

The preparation of3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid was the same as that of4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid. 35 mg, as a yellow solid, Y: 44%. ESI-MS (M+H)⁺: 422.3, HPLC:97.51%. ¹H NMR (400 MHz, CD₃OD) δ: 7.82 (s, 1H), 7.79-7.75 (m, 2H), 7.44(dd, J=8.4, 1.2 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 7.14 (dd, J=8.8, 2.0Hz, 1H), 4.35-4.32 (m, 1H), 4.28 (s, 2H), 3.44-3.36 (m, 4H), 2.26-2.23(m, 2H), 2.17-2.15 (m, 2H), 1.94-1.87 (m, 3H), 1.43-1.35 (m, 2H),1.28-1.22 (m, 2H), 1.12-1.06 (m, 1H), 0.90 (s, 9H).

Example 694-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid Step 1: methyl4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate

The solution of6-((trans-4-(tert-butyl)cyclohexyl)oxy)quinoline-2-carbaldehyde (200 mg,0.6 mmol) and methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (142 mg,0.644 mmol) in Ethanol (2 mL, 30 mmol) was heated to reflux for 2 h. Theyellow solution was cooled to room temperature and sodiumcyanoborohydride (48.6 mg, 0.773 mmol) was added and was heated toreflux for 1 h. After cooled down to room temperature, citric acid wasadded and concentrated down. The solid was suspended in water andfiltrate, and the collected solid was washed thoroughly with water. HPLCpurification of the solid give the product (62.7 mg, 20%). LCMS Rt=1.67min, m/z=479.30 [M+1]. Lithium hydroxide (15.7 mg, 0.655 mmol) was addedto a solution of4-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-amino}-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (62.7 mg, 0.131 mmol) in tetrahydrofuran (0.8 mL, 10mmol) and methanol (0.8 mL, 20 mmol). The mixture was stirred at 50° C.overnight. the solvent was concentrated. The residue was taken up inDMSO and conc. HCl (200 uL) was added to solubilize. Purification bypreparative HPLC gave the product as a white solid (63 mg, 20%). LCMS(100%, RT=1.57 min, m/z=465.30. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 0.94(s, 9H) 1.06-1.60 (m, 5H), 1.86-1.99 (m, 2H), 2.00-2.10 (m, 12H),2.24-2.37 (m, 2H) 4.32-4.46 (m, 1H) 4.49 (s, 2H) 7.34 (d, J=2.51 Hz, 1H)7.42 (dd, J=9.29, 2.76 Hz, 1H), 7.47 (d, J=8.53 Hz, 1H) 8.01 (d, J=9.29Hz, 1H) 8.28 (d, J=8.28 Hz, 1H).

Step 2:4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)quinolin-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

Lithium hydroxide (15.7 mg, 0.655 mmol) was added to a solution of4-{[6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-ylmethyl]-amino}-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (62.7 mg, 0.131 mmol) in tetrahydrofuran (0.8 mL, 10mmol) and methanol (0.8 mL, 20 mmol). The mixture was stirred at 50° C.overnight. the solvent was concentrated. The residue was taken up inDMSO and conc. HCl (200 uL) was added to solubilize. Purification bypreparative HPLC gave the product as a white solid (2.3 mg, 4%). LCMS(100%, RT=1.57 min, m/z=465.30. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.94(s, 9H) 1.06-1.60 (m, 5H), 1.86-1.99 (m, 2H), 2.00-2.10 (m, 12H),2.24-2.37 (m, 2H) 4.32-4.46 (m, 1H) 4.49 (s, 2H) 7.34 (d, J=2.51 Hz, 1H)7.42 (dd, J=9.29, 2.76 Hz, 1H), 7.47 (d, J=8.53 Hz, 1H) 8.01 (d, J=9.29Hz, 1H) 8.28 (d, J=8.28 Hz, 1H).

Example 704-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)(methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

4-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (223 mg, 0.467 mmol) and paraformaldehyde (80 mg, 3mmol) in ethanol (2 mL, 30 mmol) was heated to 80° C. for 1 h, thensodium cyanoborohydride (80 mg, 1 mmol) was added and was heated to 80°C. for 1 h. After concentration, the residue was participated in EtOAcand Aq NaHCO₃. The collected organic layer was washed with brine anddried over Na₂SO₄. The residue was purified by chromatography with Sigel under MeOH/DCM gave product (173.2 mg, 75%). LCMS Rt=1.75 min,m/z=492.20.

2 M of lithium hydroxide, monohydrate in water (0.788 mL, 1.58 mmol) wasadded to a solution of4-{[6-(trans-4-tert-butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-methyl-amino}-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (0.075 g, 0.15 mmol) in tetrahydrofuran (0.788 mL,9.71 mmol) and methanol (0.788 mL, 19.4 mmol). The mixture was stirredat 50° C. overnight. The solvent was concentrated. The residue was takenup in MeOH and conc. HCl (200 uL) was added. The precipitate was washedthoroughly with water and dry over vacuum to give4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)(methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid (100 mg, 100%). LCMS (100%, RT=1.68 min, m/z=478.20). ¹H NMR (400MHz, METHANOL-d4) δ 7.93 (s, 1H), 7.89 (d, J=8.60 Hz, 1H), 7.84 (d,J=9.04 Hz, 1H), 7.49 (dd, J=1.85, 8.50 Hz, 1H), 7.32 (d, J=2.38 Hz, 1H),7.21 (dd, J=2.51, 8.97 Hz, 1H), 4.40 (tt, J=4.27, 10.75 Hz, 1H), 3.75(m, 2H), 2.70 (s, 3H), 2.30 (d, J=11.92 Hz, 2H), 2.10 (br. s., 12H),1.94 (d, J=13.43 Hz, 2H), 1.05-1.54 (m, 5H), 0.94 (s, 9H).

Example 718-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The preparation of8-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid was the same as that of3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid, 6.7 mg, as a yellow solid, Y: 34%. LCMS (100%, RT=1.65 min,m/z=450.20). ¹H NMR (400 MHz, METHANOL-d₄) δ 7.92 (s, 1H), 7.88 (d,J=8.60 Hz, 1H), 7.82 (d, J=9.04 Hz, 1H), 7.51 (d, J=8.53 Hz, 1H), 7.31(s, 1H), 7.19 (dd, J=2.48, 8.94 Hz, 1H), 4.37-4.48 (m, 1H), 4.28-4.36(m, 2H), 3.43 (s, 2H), 1.06-2.64 (m, 18H), 0.94 (s, 9H).

Example 729-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The preparation of9-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid was the same as that of3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid, 237 mg, as a yellow solid, Y: 68%. LCMS (100%, RT=1.66 min,m/z=464.20). ¹H NMR (400 MHz, METHANOL-d₄) δ 8.01 (d, J=4.20 Hz, 1H),7.89 (d, J=8.41 Hz, 1H), 7.84 (d, J=9.16 Hz, 1H), 7.59 (d, J=8.41 Hz,1H), 7.31 (s, 1H), 7.15-7.25 (m, 1H), 4.61-4.79 (m, 2H), 4.30-4.49 (m,1H), 3.37-3.78 (m, 2H), 1.06-2.77 (m, 20H), 0.94 (s, 9H).

Example 733-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylicacid

The preparation of9-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid was the same as that of3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid, 150 mg, as a yellow solid, Y: 29%. LCMS Rt=1.69 min, m/z=464.20[M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.94-8.03 (m, 1H), 7.90 (d,J=7.97 Hz, 1H), 7.85 (d, J=9.04 Hz, 1H), 7.47-7.62 (m, 1H), 7.33 (br.s., 1H), 7.22 (d, J=8.97 Hz, 1H), 4.46 (d, J=14.31 Hz, 2H), 4.28-4.41(m, OH), 3.39-3.67 (m, 2H), 1.04-3.04 (m, 20H), 0.94 (s, 9H).

Example 743-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.1]heptane-6-carboxylicacid

The preparation of3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.1]heptane-6-carboxylicacid was the same as that of3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid, 150 mg, as a yellow solid, Y: 29%. LCMS Rt=1.69 min, m/z=436.3[M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.94-8.03 (m, 1H), 7.90 (d,J=7.97 Hz, 1H), 7.85 (d, J=9.04 Hz, 1H), 7.47-7.62 (m, 1H), 7.33 (br.s., 1H), 7.22 (d, J=8.97 Hz, 1H), 4.46 (d, J=14.31 Hz, 2H), 4.28-4.41(m, OH), 3.39-3.67 (m, 2H), 1.04-3.04 (m, 20H), 0.94 (s, 9H).

Example 754-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylicacid

The preparation of4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylicacid was the same as that of3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid, 64 mg, as a yellow solid, Y: 37%. LCMS (100%, RT=1.63 min,m/z=450.30). ¹H NMR (400 MHz, METHANOL-d4) δ 7.92 (s, 1H), 7.88 (d,J=8.41 Hz, 1H), 7.82 (d, J=9.16 Hz, 1H), 7.51 (dd, J=1.85, 8.50 Hz, 1H),7.31 (d, J=2.26 Hz, 1H), 7.20 (dd, J=2.48, 9.00 Hz, 1H), 4.38-4.46 (m,1H), 4.37 (s, 2H), 1.82-2.36 (m, 14H), 1.03-1.55 (m, 5H), 0.94 (s, 9H).

Example 764-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid

The preparation of4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylicacid was the same as that of3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid, 32 mg, as a yellow solid, Y: 19%. LCMS (100%, RT=1.73 min,m/z=519.30). ¹H NMR (400 MHz, METHANOL-d4) δ 8.26 (dd, J=1.63, 9.04 Hz,1H), 8.13 (d, J=9.29 Hz, 1H), 8.05 (d, J=1.82 Hz, 1H), 7.67 (dd, J=2.07,9.10 Hz, 1H), 7.61 (d, J=9.29 Hz, 1H), 4.46-4.57 (m, 1H), 4.41 (s, 2H),2.23 (dd, J=3.20, 9.91 Hz, 4H), 1.98-2.16 (m, 6H), 1.93 (d, J=10.67 Hz,4H), 1.44-1.62 (m, 2H), 1.04-1.34 (m, 3H), 0.93 (s, 9H).

Example 774-((6-(trans-4-(Trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylicacid Step 1: (4-methoxyphenyl)trimethylsilane

4-Bromoanisole (9.35 g, 50.0 mmol, 1.0 eq) was dissolved in anhydrousTHF (200 mL). Me₃SiCl (12.7 mL, 100.0 mmol, 2.0 eq) was added at 0° C.followed by n-BuLi (2.5 M in hexanes, 40 mL, 100.0 mmol, 2.0 eq). Thereaction mixture was stirred at room temperature for 1 h. Water (150 mL)was then added, the organic layer was separated and the aqueous layerwas extracted with Et₂O (150 mL×2). The combined organic extracts weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give(4-methoxyphenyl)trimethylsilane as a light yellow oil (8.1 g, 90%yield). ¹H NMR (300 MHz, CDCl₃) δ: 7.48 (d, J=11.2 Hz, 2H), 6.95 (d,J=11.2 Hz, 2H), 3.84 (s, 3H), 0.27 (s, 9H).

Step 2: 4-(Trimethylsilyl)cyclohexanone

Ammonia (100 mL) was condensed at −78° C.(4-methoxyphenyl)trimethylsilane (18.0 g, 0.1 mol, 1.0 eq) in anhydrousEt₂O (110 mL) was added followed by EtOH (80 mL) and sodium (23.0 g, 1.0mol, 10.0 eq) portionwise at −33° C. Additional EtOH ((50 mL) was addedand ammonia was allowed to evaporated over 16 h. The water (250 mL) wasadded to the residue and the mixture was extracted with Et₂O (250 mL×3).The combined organic extracts were dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The crude product was dissolved in EtOH (20mL) and H₂O (20 mL) and oxalic acid (2.71 g, 0.03 mol, 0.3 eq) was thenadded. The resulting colorless solution was stirred at room temperaturefor 2 h. Water (100 mL) was then added and the mixture was extractedwith Et₂O (100 mL×3). The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by column chromatography on silica gel(petroleum ether/EtOAc=10:1) to furnish 4-(trimethylsilyl)cyclohexanoneas a light yellow oil (14.0 g, 72% yield). ¹H NMR (300 MHz, CDCl₃) δ:2.44-2.39 (m, 2H), 2.33-2.22 (m, 2H), 2.11-2.05 (m, 2H), 1.53-1.47 (m,2H), 0.96-0.87 (m, 1H), 0.00 (s, 9H).

Step 3: cis-4-(Trimethylsilyl)cyclohexanol

To a solution of L-selectride (165 mL, 0.165 mol, 1.5 eq) in anhydrousTHF (200 mL) at −78° C. was added dropwise a solution of4-(trimethylsilyl)cyclohexanone (20 g, 0.11 mol, 1.0 eq) in anhydrousTHF (100 mL). The temperature was maintained for 3 h, and then thereaction mixture was stirred at room temperature for 16 h. Then themixture was cooled to 0° C. before being quenched with water. Theresulting mixture was warmed up to room temperature, and then sodiumhydroxide aqueous solution (80 mL, 3 M) was added, followed by hydrogenperoxide (80 mL, 30%). After being stirred for 3 h, the mixture wasextracted with EtOAc (300 mL×3), and the combined organic layers werewashed with H₂O and brine, dried over Na₂SO₄, concentrated to give aresidue which was purified by column chromatography on silica gel(petroleum ether/EtOAc=10:1) to obtain the productcis-4-(trimethylsilyl)cyclohexanol as a white solid (10.0 g, 51% yield).¹H NMR (300 MHz, CDCl₃) δ: 4.05 (s, 1H), 1.75 (bs, 2H), 1.58-1.43 (m,7H), 0.55 (bs, 1H), 0.00 (s, 9H).

Step 4: cis-4-(Trimethylsilyl)cyclohexyl methanesulfonate

To a solution of cis-4-(trimethylsilyl)cyclohexanol (344 mg, 2.0 mmol,1.0 eq) and Et₃N (242 mg, 2.4 mmol, 1.2 eq) in DCM (10 mL) was addedMs₂O (418 mg, 2.4 mmol, 1.2 eq) at 0° C. The resulting solution wasallowed to warm up to rt and stirred for 4 h. The mixture was thendiluted with DCM (30 mL), washed with brine (10 mL×2), dried overanhydrous sodium sulfate and filtered. The filtrate was concentratedunder reduced pressure to give the crude productcis-4-(trimethylsilyl)cyclohexyl methanesulfonate as a yellow oil (415mg, 83% yield), which was used in next step without furtherpurification. LCMS: m/z 251.3 [M+H]⁺

Step 5: Methyl 4-((6-hydroxynaphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylate

6-Hydroxy-2-naphthaldehyde (520 mg, 3.02 mmol, 1.0 eq) and methyl4-aminobicyclo[2.2.2]octane-1-carboxylate (663 mg, 3.62 mmol, 1.2 eq)were dissolved in toluene (100 mL). MgSO₄ (72 mg, 0.60 mmol, 0.2 eq) wasadded to the solution and refluxed for 48 h. The solvent was removed invacuo. The residue was dissolved in THF (150 mL) and NaBH₃CN (571 mg,9.06 mmol, 3.0 eq) was added thereto. The mixture was refluxed for 24 h.The solvent was then removed in vacuo, and the residue was diluted withwater (50 mL), extracted with EtOAc (150 mL×2). The combined organiclayers were washed with brine (70 mL) and dried over Na₂SO₄. The organicphase was concentrated in vacuo to give methyl4-((6-hydroxynaphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylateas yellow solid (819 mg, 80% yield). ¹H NMR (400 MHz, CDCl₃) δ: 9.98 (s,1H), 7.89 (s, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.47(dd, J=8.4, 1.6 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 4.17 (s, 2H), 3.60 (s,3H), 1.91-1.87 (m, 12H); ESI-MS (M+H)⁺: 340.2.

Step 6: Methyl4-((6-(trans-4-(trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylate

A mixture of methyl4-((6-hydroxynaphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylate(339 mg, 1.0 mmol, 1.0 eq), cis-4-(trimethylsilyl)cyclohexylmethanesulfonate (500 mg, 2.0 mmol, 2.0 eq) and NaOH (80 mg, 2.0 mmol,2.0 eq) in DMF (2 mL) was heated to 80° C. and stirred for 2 h. Thereaction mixture was then diluted with H₂O (5 mL) and adjusted to pH=6with dilute HCl. The resulting mixture was purified by prep-HPLC(MeOH/H₂O with 0.05% TFA as mobile phase; from 20% to 95%) to furnishmethyl4-((6-(trans-4-(trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylate169 mg (34% yield) as a light yellow oil. LCMS: m/z 494.3 [M+H]+.

Step 7:4-((6-(trans-4-(Trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylicacid

To a solution of methyl4-((6-(trans-4-(trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylate(169 mg, 0.34 mmol, 1.0 eq) in a mixed solvents (EtOH/H₂O=5:1, 6 mL) wasadded NaOH (68 mg, 1.7 mmol, 5.0 eq). The resulting solution was heatedto reflux for 1 h. After cooling down to rt, the mixture was adjusted topH=6.0 and purified with prep-HPLC (MeOH/H₂O with 10 mM NH₄HCO₃ asmobile phase; from 20% to 95%) to afford the title compound as a whitesolid (105 mg, 67% yield).

¹H NMR (400 MHz, DMSO-d₆) δ: 7.76-7.70 (m, 3H), 7.42 (d, J=10.0 Hz, 1H),7.32 (s, 1H), 7.10 (dd, J=2.4, 8.8 Hz, 1H), 4.39-4.37 (m, 1H), 3.75 (s,2H), 2.25-2.19 (m, 2H), 1.85-1.74 (m, 8H), 1.63-1.56 (m, 6H), 1.34-1.25(m, 4H), 0.56-0.52 (m, 1H), 0.01 (s, 9); LCMS m/z 480.3 [M+H]+.

Example 784-(((6-((cis-4-(Trimethylsilyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid Step 1: trans-4-(trimethylsilyl)cyclohexanol

A 500-ml round-bottomed flask was placed with LiAlH₄ (1.8 g, 50 mmol,0.75 eq) and anhydrous ether (150 mL). To this mixture was addeddropwise a solution of 4-(trimethylsilyl)cyclohexanone (11.3 g, 66 mmol,1.0 eq) in ether (75 mL). After the addition, the mixture was stirred atroom temperature for 4 h; then the reaction was quenched carefully withdilute hydrochloric acid (2 M). The aqueous layer was extracted withether (3×250 mL), the combined ether solutions were dried over magnesiumsulfate, and the ether was removed under reduced pressure to give theresidue, which was purified by column chromatogram (Petroleumether/EtOAc=10:1) to obtain the title compound as a white solid (9.2 g,45% yield). ¹H NMR (300 MHz, CDCl₃) δ: 3.58-3.52 (m, 1H), 2.09-2.06 (m,2H), 1.83-1.79 (m, 2H), 1.29-1.13 (m, 5H), 0.50-0.42 (m, 1H), 0.00 (s,9H).

Step 2: trans-4-(Trimethylsilyl)cyclohexyl methanesulfonate

Following the same condition as in Step 4 of Example 77 (cis analog),the title compound was obtained as a yellow oil (350 mg, 20% yield).LCMS: m/z 251.1 [M+H]⁺.

Step 3:4-(((6-((cis-4-(Trimethylsilyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

Using trans-4-(trimethylsilyl)cyclohexyl methanesulfonate, and followingthe same displacement and hydrolysis conditions as in Steps 6-7 ofExample 77 (trans analog), the title compound was obtained as a whitesolid (10 mg, 53% yield). LCMS m/z 480.2 [M+H]⁺; H NMR (400 MHz,DMSO-d₆, CD₃OD) δ: 7.86-7.80 (m, 3H), 7.47 (d, J=8.0 Hz, 1H), 7.26 (d,J=2.0 Hz, 1H), 7.21 (dd, J=2.0, 8.4 Hz, 1H), 4.55 (bs, 1H), 4.15 (bs,2H), 2.16-2.12 (m, 2H), 1.96-1.89 (m, 12H), 1.66-1.61 (m, 6H), 0.75-0.70(m, 1H), 0.01 (s, 9).

Example 804-((6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylicacid Step 1: Ethyl4-(benzylamino)-2-oxobicyclo[2.2.2]octane-1-carboxylate

Ethyl 1-acetyl-4-oxocyclohexanecarboxylate (4.3 g, 20.0 mmol, 1.0 eq),PTSA (350 mg, 2.0 mmol, 0.1 eq) and benzylamine (2.4 g, 22.0 mmol, 1.1eq) were dissolved in toluene (250 mL). The mixture was heated to refluxwith dean stark trap for 24 h. The mixture was diluted with H₂O (500 mL)and extracted with EtOAc (500 mL×2). The combined organic layers weredried over anhydrous Na₂SO₄ and filtered, concentrated in vacuo to yielda crude product, which was purified by column chromatography on silicagel (DCM/MeOH=20:1), then followed by recrystallization from petroleumether and ErtOAc to give the title compound as a yellow solid (1.3 g, Y:20%). LCMS m/z 302.2 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ: 9.68 (bs, 1H),7.35 (bs, 5H), 4.23 (q, J=7.2 Hz, 2H), 3.85 (s, 2H), 2.55 (s, 2H),2.23-2.17 (m, 2H), 1.93-1.64 (m, 6H), 1.30 (t, J=7.2 Hz, 3H).

Step 2: Ethyl 4-amino-2-oxobicyclo[2.2.2]octane-1-carboxylate

A solution of ethyl4-(benzylamino)-2-oxobicyclo[2.2.2]octane-1-carboxylate (500 mg, 1.66mmol, 1.0 eq) in MeOH (10 mL) was purged with N₂ for 3 times. Pd/C (50mg, 10% w/w) was added, and the mixture was purged with H₂ for 2 times.The resulting mixture was stirred at rt under a H₂ balloon for 16 h, andthen filtered. The filtrate was concentrated in vacuo to get the titlecompound (280 mg 80%) as a white solid. LCMS m/z 212.1 [M+H]+; ¹H NMR(400 MHz, DMSO-d₆) δ: 8.42 (bs, 2H), 4.10 (q, J=7.2 Hz, 2H), 2.63 (bs,2H), 2.15-1.89 (m, 8H), 1.17 (t, J=7.2 Hz, 3H).

Step 3: Ethyl 4-amino-2-hydroxybicyclo[2.2.2]octane-1-carboxylate

A mixture of ethyl 4-amino-2-oxobicyclo[2.2.2]octane-1-carboxylate (200mg, 0.47 mmol, 1.0 eq) and NaBH₄ (18 mg, 0.47 mmol, 1.0 eq) in EtOH (10mL) was stirred at 0° C. for 30 min. Then the reaction was quenched withwater (5 mL) and extracted with EtOAc (8 mL×3). The organic phase wasconcentrated in vacuo to give the title compound as a white solid (163mg, 41% yield), which was used in next step without furtherpurification. LCMS m/z 214.1 [M+H]⁺.

Step 4: Ethyl4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylate

A mixture of ethyl 4-amino-2-hydroxybicyclo[2.2.2]octane-1-carboxylate(163 mg, 0.77 mol, 1.0 eq),6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (239 mg, 0.77 mmol,1.0 eq) and AcOH (139 mg, 2.31 mmol, 3.0 eq) in DCE (5 mL) was heated toreflux for 30 min. After cooling down to rt, NaBH(OAc)₃ (490 mg, 2.31mmol, 3.0 eq) was added and the mixture was stirred for additional 16 hat rt. The reaction was then quenched with water (5 mL) and extractedwith DCM (5 mL×3). The combined organic phase was concentrated in vacuo,and the residue was purified by prep-HPLC (MeOH/H₂O from 30% to 95%,containing 0.05% TFA) to give the title compound as a white solid (169mg, 35% yield). LCMS m/z 508.3 [M+1]⁺;

Step 5:4-((6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylicacid

To a mixture of ethyl4-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylate(169 mg, 0.33 mmol, 1.0 eq) in a mixed solvent (EtOH/H₂O=4:1, 5 mL) wasadded NaOH (26 mg, 0.66 mmol, 2.0 eq), the resulting mixture was heatedto reflux for 16 h. After cooling down to rt, the reaction mixture wasthen adjusted to pH=6 with dilute aq. HCl (2 M). The resultingsuspension was filtered, and the filtrate was purified by prep-HPLC(MeOH/H₂O from 30% to 95%, containing 0.05% TFA) to yield the titlecompound as a yellow solid (84 mg, 52% yield). LCMS m/z 480.3 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ: 7.82-7.76 (m, 3H), 7.48 (d, J=8.4 Hz, 1H),7.35 (d, J=2.4 Hz, 1H), 7.13 (dd, J=8.8, 2.4 Hz, 1H), 4.37-4.36 (m, 1H),4.10-4.08 (m, 1H), 3.96 (s, 2H), 2.21-2.11 (m, 4H), 1.83-1.55 (m, 10H),1.36-1.07 (m, 5H), 0.88 (s, 9H).

Example 814-((6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl)methylamino)-1-(hydroxymethyl)bicyclo[2.2.2]octan-2-olStep 1: 4-Amino-1-(hydroxymethyl)bicyclo[2.2.2]octan-2-ol

To a mixture of ethyl 4-amino-2-oxobicyclo[2.2.2]octane-1-carboxylate(200 mg, 0.47 mmol, 1.0 eq) in EtOH (10 mL) was added NaBH₄ (71 mg, 1.88mmol, 4.0 eq) at 0° C., and the resulting mixture was stirred for 30min. The reaction was then quenched with water (5 mL) and extracted withEtOAc (3×8 mL). The combined organic layers were concentrated in vacuoto give the title compound as a white solid (130 mg 56% yield), whichwas used for the next step without further purification. LCMS m/z 172.1[M+H]+;

Step 2:4-((6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl)methylamino)-1-(hydroxymethyl)bicyclo[2.2.2]octan-2-ol

A mixture of 4-amino-1-(hydroxymethyl)bicyclo[2.2.2]octan-2-ol (130 mg,0.76 mol, 1.0 eq), 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde(235 mg, 0.76 mmol, 1.0 eq) and HOAc (137 mg, 2.28 mmol, 3.0 eq) in DCM(5 mL) was heated to reflux for 30 min. After cooling down to rt,NaBH(OAc)₃ (483 mg, 2.28 mmol, 3.0 eq) was added and the mixture wasstirred for additional 16 h at rt. Then the reaction was quenched withwater (5 mL) and extracted by DCM (3×5 mL). The organic phase wasconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O from 30% to95%, containing 0.05% TFA) to give the title compound as a white solid(39 mg, 14% yield). LCMS m/z 466.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ:8.70 (bs, 2H), 7.92 (s, 1H), 7.87-7.82 (m, 2H), 7.52 (d, J=8.4 Hz, 1H),7.41 (d, J=2.4 Hz, 1H), 7.19 (dd, J=8.8, 2.8 Hz, 1H), 4.84 (bs, 1H),4.40-4.39 (m, 1H), 4.18 (bs, 2H), 3.81-3.79 (m, 1H), 3.28 (d, J=10.4 Hz,1H), 3.12 (d, J=10.8 Hz, 1H), 2.21-2.19 (m, 3H), 1.84-1.08 (m, 16H),0.88 (s, 9H).

Example 824-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid Step 1:4-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester

A solution of 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde(238 mg, 0.767 mmol) (WO 2011/017561 A1) and methyl4-aminobicyclo[2.2.2]octane-1-carboxylate (168 mg, 0.767 mmol) (PrimeOrganics) in Ethanol (2 mL, 30 mmol) was heated to reflux for 2 h. Theyellow solution was cooled to room temperature and Sodiumcyanoborohydride (57.8 mg, 0.920 mmol) was added and heated to refluxfor 3d. The mixture was cooled and concentrated. The solid was suspendedin aqueous NaHCO3 and EtOAc, The organic layer was washed with brine,dried and concentrated. Column chromatography in Silica gel withMeOH/DCM gives a solid as the product (217 mg, 59% yield). LCMS: Rt=1.69min m/z 478.30 [M+1]. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.88-0.95 (m,9H) 1.02-1.35 (m, 9H) 1.35-1.54 (m, 2H) 1.60-1.73 (m, 6H) 1.75-1.87 (m,6H) 1.90 (d, J=12.99 Hz, 2H) 2.27 (d, J=11.67 Hz, 2H) 3.66 (s, 3H) 3.85(s, 2H) 4.17-4.35 (m, 1H) 7.02-7.17 (m, 2H) 7.39 (d, J=8.41 Hz, 1H)7.61-7.78 (m, 3H).

Step 2:4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid

2 M Lithium hydroxide, monohydrate in Water (2 mL, 4 mmol) was added toa solution of4-{[6-(trans-4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]octane-1-carboxylicacid methyl ester (217 mg, 0.454 mmol) in Tetrahydrofuran (2 mL, 20mmol) and Methanol (1 mL, 20 mmol). The mixture was stirred at 70° C.overnight. The solvent was concentrated. The residue was taken up inDMSO and TFA (200 μL) was added to solubilize. Purification bypreparative HPLC gave the product (135 mg, 64%). HPLC (100%, RT=1.483min), LCMS (100%, RT=1.64 min, m/z=464.30). ¹H NMR (400 MHz,METHANOL-d4) δ ppm 0.94 (s, 9H) 1.03-1.56 (m, 5H) 1.94 (d, J=14.56 Hz,2H) 2.03 (d, J=7.03 Hz, 12H) 2.29 (d, J=11.23 Hz, 2H) 4.27 (s, 2H)4.33-4.46 (m, 1H) 7.19 (d, J=11.36 Hz, 1H) 7.30 (s, 1H) 7.49 (d, J=8.41Hz, 1H) 7.82 (d, J=8.97 Hz, 1H) 7.87 (d, J=8.60 Hz, 1H) 7.90 (s, 1H).

Example 839-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

To a mixture of 9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid methylester HCl salt (26 mg, 0.12 mmol) and6-((cis-4-ethylcyclohexyl)oxy)-2-naphthaldehyde (28 mg, 0.10 mmol) inTHF (0.6 mL) was added sodium triacetoxyborohydride (30 mg, 0.14 mmol).The reaction solution was heated with microwave irritation at 100° C.for 20 min. To the above mixture was added 3 M of NaOH in water (0.5 mL,2 mmol) and MeOH (0.8 mL). It was heated with microwave irritation at100° C. for 10 min. Neutralized with 1N HCl, filtered and purified byHPLC (TFA method) to collect the desired acid as a white powdered afterlyophilization (30 mg, yield 54% for two steps). ¹H NMR (400 MHz,METHANOL-d₄) δ 8.00 (br. S., 1H), 7.78-7.90 (m, 2H), 7.57 (d, J=8.53 Hz,1H), 7.29 (d, J=2.01 Hz, 1H), 7.23 (dd, J=2.38, 8.91 Hz, 1H), 4.52-4.78(m, 3H), 3.58-3.70 (m, 2H), 3.35-3.47 (m, 1H), 2.47-2.69 (m, 2H),1.82-2.35 (m, 9H), 1.24-1.79 (m, 10H), 0.93 (t, J=7.15 Hz, 3H); LCMS m/z436.1 [M+H]⁺

Example 849-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1: 4-(trifluoromethyl)cyclohexyl methanesulfonate

To a solution of 4-trifluoromethyl-cyclohexanol (20.0 g, 119 mmol,mixture of cis/trans, ˜20/80, Youchemicals), and triethylamine (22 mL,155 mmol) in methylene chloride (300.0 mL) was added methanesulfonylchloride (12 mL, 155 mmol) dropwise at 0° C. A white precipitate formed.The reaction mixture was stirred from 0° C. to RT overnight. The mixturewas diluted with dichloromethane and washed with citric acid (5% inwater), sodium bicarbonate aqueous solution and water, dried oversulfate, filtered, concentrated and dried overnight on the lyophilizerand collected to give the titled compound as a white solid (23.9 g, 82%,a mixture of cis and trans, ratio is ˜20/80 based on the NMR); 1H NMR(400 MHz, CHLOROFORM-d) δ 4.50-5.13 (m, 1H), 3.05 (s, 3H), 1.94-2.37 (m,4H), 1.35-1.91 (m, 5H).

Step 2: 6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthaldehyde and6-((trans-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthaldehyde

To a mixture of 6-hydroxy-naphthalene-2-carbaldehyde (4.0 g, 23 mmol)and cesium carbonate (15.14 g, 46 mmol) in N,N-dimethylformamide (100mL) was added methanesulfonic acid 4-trifluoromethyl-cyclohexyl ester(11 g, 46 mmol) in two portions (the second portion was added afterheating for 4 h). The resulting mixture was heated at 85° C. overnight.Diluted with ethyl acetate, washed with water, brine and dried oversodium sulfate. The crude mixture was then purified by ISCO columnchromatography (ethyl acetate/heptane gradient 0% to 30%) to give twoisomers (2.95 g, 39% of cis-isomer and 1.23 g, 16% of trans-isomer). Forcis-isomer: LCMS: RT 2.01, MH+ 323.1, ¹H NMR (400 MHz, CHLOROFORM-d) δ10.10 (s, 1H), 8.26 (s, 1H), 7.93 (d, J=8.78 Hz, 2H), 7.78 (d, J=8.53Hz, 1H), 7.25-7.30 (m, 1H), 7.20 (d, J=2.01 Hz, 1H), 4.76-4.86 (m, 1H),2.28 (d, J=14.81 Hz, 2H), 2.07-2.22 (m, 1H), 1.75-1.92 (m, 4H),1.61-1.72 (m, 2H); For trans-isomer: LCMS: RT 2.00 min; MH+ 323.1; ¹HNMR (400 MHz, CHLOROFORM-d) δ 10.10 (s, 1H), 8.26 (s, 1H), 7.86-7.97 (m,2H), 7.79 (d, J=8.53 Hz, 1H), 7.14-7.24 (m, 2H), 4.32-4.50 (m, 1H), 2.37(d, J=5.77 Hz, 2H), 2.12 (d, J=6.02 Hz, 3H), 1.47-1.58 (m, 4H).

Step 3:5-iodo-6-(cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthaldehyde

To a mixture of6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthaldehyde (3.0 g, 9.31mmol) and zirconium chloride (0.30 g, 1.86 mmol) in methylene chloride(60 mL) was added N-iodosuccinimide (2.51 g, 11.2 mmol). The reactionwas then stirred at RT overnight. LC-MS showed complete conversion andthe formation of the desired product. Worked up with aqueous sodiumthiosulfate and ethyl acetate, the organic extracts were washed withsodium bicarbonate and dried over magnesium sulfate, and concentrated.The product was recrystallized from methanol to give the titled compoundas a light yellow solid (4.06 g, 97%). LCMS: RT: 2.18 min., MH+ 449.0;¹H NMR (400 MHz, CHLOROFORM-d) δ 10.15 (s, 1H), 8.20-8.31 (m, 2H),7.92-8.02 (m, 2H), 7.24 (d, J=9.04 Hz, 1H), 4.94 (br. S., 1H), 1.98-2.30(m, 5H), 1.76-1.89 (m, 2H), 1.64 (t, J=14.06 Hz, 2H).

Step 4:5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthaldehyde

According to the procedure reported in WO 2006/057869, by Aicher,Thomas. D. et al. (which is incorporated by reference in its entirety),a solution of5-iodo-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalene-2-carbaldehyde(4.0 g, 8.9 mmol), hexamethylphosphoramide (7.8 mL, 44.6 mmol) inN,N-dimethylformamide (40 mL) was degassed with Ar. To this was addedcopper(I) iodide (3.06 g, 16.1 mmol) and methylfluorosulphonyldifluoroacetate (5.8 mL, 44.6 mmol) and the reaction wasstirred at 85° C. under an atmosphere of argon. After stirring for 5hours, LCMS showed no starting material left and the formation of thedesired product. The reaction mixture was diluted with ethyl acetate,and washed with water (5×). The organic layer was then dried over MgSO4,concentrated. The solid was then crystallized from methanol to give theproduct as a white powder (1.88 g, 54%). ¹H NMR (400 MHz, DMSO-d6) δ10.12 (s, 1H), 8.63 (d, J=1.51 Hz, 1H), 8.45 (d, J=9.29 Hz, 1H), 8.21(d, J=8.28 Hz, 1H), 8.02 (dd, J=1.76, 9.04 Hz, 1H), 7.79 (d, J=9.29 Hz,1H), 5.17 (br. S., 1H), 2.35-2.47 (m, 1H), 2.07 (d, J=13.55 Hz, 2H),1.53-1.85 (m, 6H); ESI-MS (M+H)⁺: 391.10

Step 5:9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

A mixture of 9-Aza-bicyclo[3.3.1]nonane-3-carboxylic acid methyl esterhydrochloride (Advanced Chemblocks, 63 mg, 0.29 mmol) and triethylamine(34 uL, 0.24 mmol) in 1,2-dichloroethane (2.00 mL) was stirred at rt for20 min.5-Trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalene-2-carbaldehyde(80.0 mg, 0.20 mmol) was then added. The reaction was then stirred at50° C. for 1 h, cooled down, sodium triacetoxyborohydride (70 mg, 0.33mmol) was added, and the reaction was stirred at rt overnight. LCMSshowed the formation of methyl9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)-oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate (RT 1.56 min.; MH+ 558.3).Worked up with ethyl acetate and brine, dried over magnesium sulfate andconcentrated. The crude was then dissolved in tetrahydrofuran (3.0 mL),1.0 M of lithium hydroxide in water (2.0 mL, 2.0 mmol) was added. Themixture was stirred at rt for 3 h. Neutralized with conc. HCl, extractedwith ethyl acetate. The organic layer was concentrated, and the crudewas purified by HPLC to give the titled compound as a white powder (49mg, TFA salt). LCMS: RT 1.47 min.; MH+ 544.2; 1H NMR (400 MHz, DMSO-d6)δ 9.36 (br. S., 1H), 8.09-8.30 (m, 3H), 7.83 (d, J=9.04 Hz, 1H), 7.71(d, J=9.29 Hz, 1H), 5.12 (br. S., 1H), 4.56-4.79 (m, 2H), 3.53 (d,J=15.56 Hz, 2H), 3.13-3.32 (m, 1H), 2.32-2.47 (m, 3H), 1.85-2.28 (m,8H), 1.50-1.82 (m, 8H).

Example 853-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)amino)spiro[3.5]nonane-1-carboxylicacid

Step 1:(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methanaminehydrochloride

A mixture of5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalene-2-carbaldehyde(5.6 g, 14.3 mmol) and hydroxylamine hydrochloride (1.5 g, 21.5 mmol) in300 mL of ethanol was stirred at RT for 5 h. To the mixture was addedcone. HCl (3 mL) and Pd/C (10%, wet, 1 g). The mixture was hydrogenatedat RT under a pressure of 5 kgf/cm² for 8 h and filtered. The filtratewas concentrated to give a residue which was washed with 20 mL of waterto afford the title compound as a light yellow solid (5.0 g, yield:82%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (br s, 3H), 8.16 (d, J=9.2 Hz,1H), 8.07-8.06 (m, 2H), 7.75 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.66 (d, J=9.2Hz, 1H), 5.08 (s, 1H), 4.15 (s, 2H), 2.49-2.41 (m, 1H), 2.05-2.02 (m,2H), 1.74-1.60 (m, 6H); ESI-MS (M-NH₂): 375.1.

Step 2:3-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)amino)spiro[3.5]nonane-1-carboxylic acid

To a mixture of(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methanamine (80 mg, 0.20 mmol) and3-oxo-spiro[3.5]nonane-1-carboxylic acid methyl ester (60 mg, 0.31 mmol)in tetrahydrofuran (2.0 mL) was added acetic acid (0.02 mL, 0.41 mmol),sodium triacetoxyborohydride (87 mg, 0.41 mmol) and titaniumtetraisopropoxide (116 mg, 0.41 mmol), and the reaction was heated inmicrowave at 100° C. for 20 min. LCMS showed formation of desired ester,methyl3-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)-oxy)naphthalene-2-yl)methyl)amino)spiro[3.5]nonane-1-carboxylate,(RT 1.66 min, MH+ 572.3). Worked up with ethyl acetate and brine, driedover magnesium sulfate and concentrated. The resulted crude was thendissolved in tetrahydrofuran (1.0 mL) and methanol (1.0 mL), treatedwith 3.0 M of sodium hydroxide in water (1.0 mL, 3.0 mmol), heated inmicrowave at 100° C. for 10 min., acidified with 2N HCl, the organicphase was dried and concentrated. The crude was purified by HPLC to givethe title compound as a white powder (15 mg). LCMS: RT 1.57 min.; MH+558.3; 1H NMR (400 MHz, METHANOL-d4) δ 8.27 (d, J=8.53 Hz, 1H), 8.14 (d,J=9.29 Hz, 1H), 8.04 (d, J=1.26 Hz, 1H), 7.68 (dd, J=1.88, 9.16 Hz, 1H),7.59 (d, J=9.29 Hz, 1H), 5.02 (br. S., 1H), 4.23-4.43 (m, 2H), 3.39 (t,J=8.41 Hz, 1H), 2.75 (t, J=8.53 Hz, 1H), 2.06-2.46 (m, 6H), 1.15-1.91(m, 15H).

Example 863-(4-{[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]oct-1-yl)-propionicacid

The title compound was prepared according to the procedure described forExample 84 from methyl 3-(4-aminobicyclo[2.2.2]octan-1-yl)propanoate and5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalene-2-carbaldehyde.¹H NMR (400 MHz, DMSO-d6) δ 8.77 (br. S., 2H), 8.22 (d, J=9.54 Hz, 1H),8.04-8.16 (m, 2H), 7.64-7.76 (m, 2H), 5.10 (br. S., 1H), 4.15-4.30 (m,2H), 2.35-2.46 (m, 1H), 2.10-2.19 (m, 2H), 1.98-2.09 (m, 2H), 1.79-1.93(m, 6H), 1.57-1.78 (m, 6H), 1.44-1.55 (m, 6H), 1.33-1.43 (m, 2H);ESI/MH+ 572.3

Example 873-(4-(methyl((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)amino)bicyclo[2.2.2]octan-1-yl)propanoicacid

To a mixture of3-(4-{[5-Trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]oct-1-yl)-propionicacid (35.0 mg, 0.06 mmol) and acetic acid (0.1 mL, 2 mmol) in 37%formaldehyde in water (1.5 mL, 2.0E1 mmol) and methanol (0.5 mL, 10mmol) was stirred at 50° C. for 1 h. Sodium triacetoxyborohydride (26mg, 0.12 mmol) was then added. The reaction was then stirred at RT for 2h. The reaction mixture was concentrated under reduced pressure. Thecrude was purified by HPLC to give the title compound as a white powder(24 mg). LCMS: RT 1.52 min.; MH+ 586.3; 1H NMR (400 MHz, METHANOL-d4) δ8.24-8.32 (m, 1H), 8.12-8.19 (m, 1H), 8.05 (d, J=1.51 Hz, 1H), 7.54-7.69(m, 2H), 5.03 (br. S., 1H), 4.89 (br. S., 1H), 3.99 (d, J=13.05 Hz, 1H),2.67 (s, 3H), 1.95-2.38 (m, 11H), 1.62-1.91 (m, 12H), 1.49-1.59 (m, 2H)

Example 889-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid Step 1:1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalen-2-yl)ethano

To a solution of5-Trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalene-2-carbaldehyde(3.0 g, 7.7 mmol) in dry tetrahydrofuran (50 mL) at −78° C. under argonwas dropwise added 1.4 M of methylmagnesium bromide in toluene/THF(75/25 mixture) (8.2 mL, 12 mmol). After stirred at −78° C. for 1 h,allowed the reaction mixture to warm up a little before quenched withsaturated aqueous ammonium chloride, extracted with ethyl acetate. Theorganic phase was dried, filtered and concentrated. The crude waspurified by ISCO (EtOAc/heptane gradient from 0/100 to 60/40) to givethe title product as a colorless oil (2.1 g). LC-MS: RT 1.97 min.; ESI:389.0 (M−OH) and 429.0 (M+Na). ¹H NMR (400 MHz, DMSO-d6) δ 8.17 (d,J=9.04 Hz, 1H), 7.98-8.05 (m, 1H), 7.89 (s, 1H), 7.57-7.65 (m, 2H), 5.31(d, J=4.02 Hz, 1H), 5.06 (br. S., 1H), 4.77-4.96 (m, 1H), 2.42 (br. S.,1H), 2.00-2.10 (m, 2H), 1.57-1.80 (m, 6H), 1.39 (d, J=6.53 Hz, 3H).

Step 2:6-(1-bromoethyl)-1-(trifluoromethyl)-2-((cis-4-(trifluoromethyl)cyclo-hexyl)oxy)naphthalene

To a solution of1-[5-Trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-ethanol(1.9 g, 4.7 mmol) in tetrahydrofuran (20 mL) was added 1.0 M ofphosphorus tribromide in methylene chloride (4.7 mL, 4.7 mmol). Themixture was stirred at RT for 10 min. The reaction was diluted withEtOAc, washed with water. The organic layer was then dried andconcentrated to give the title product as a colorless oil (2.1 g, with˜30% SM based on LCMS) which was used in the next step without furtherpurifications. LCMS: RT 2.37 min.; ESI: 389.0 (M-Br).

Step 3: methyl9-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)-oxy)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate

To a mixture of potassium carbonate (294 mg, 2.13 mmol) and9-Aza-bicyclo[3.3.1]-nonane-3-carboxylic acid methyl ester hydrochloride(609 mg, 2.77 mmol) in N,N-dimethylformamide (15 mL) was added asolution of6-(1-Bromo-ethyl)-1-trifluoro-methyl-2-(4-trifluoromethyl-cyclohexyloxy)-naphthalene(1.0 g, 2.1 mmol) in DMF (5 ml). The reaction mixture was stirred at RTovernight. The mixture partitioned between ethyl acetate and saturatedaqueous sodium bicarbonate. The organic phase was then washed withbrine, dried, filtered and concentrated. The crude was purified by ISCO(EtOAc/heptane, gradient 0/100 to 50/50) to give the title product as awhite powder (555 mg). LC-MS: RT 1.61 min., MH+ 572.1.

Step 4:9-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)-oxy)-naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Methyl9-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)-oxy)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate.was dissolved in tetrahydrofuran (2.0 mL) and methanol (1.0 mL). 3.0 Mof aqueous sodium hydroxide (2.0 mL, 6.0 mmol) was then added. Thereaction was heated in microwave at 100° C. for 10 min. The reactionmixture was then neutralized with 2N HCl. The organic phase wasseparated, dried and concentrated. The crude was purified by HPLC togive9-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)-oxy)-naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid as a white powder.

Example 899-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid Step 1:9-((R)-1-(5-trifluoromethyl-6-(cis-4-(trifluoromethyl)cyclohexyloxy)-naphthalen-2-yl)-ethyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid methyl ester

Racemic9-{1-[5-Trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-ethyl}-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid methyl ester (493 mg, 0.86 mmol) was sent for chiral separation (byLotus Separations). The methods: IC (2×15 cm), 25% methanol (0.1%DEA)/CO₂, 100 bar; 60 ml/min., 220 nM.; ini vol: 1 mL, 20 mg/mLmethanol. Two isomers were obtained after the chiral separation. Sincethe absolute stereo chemistry is unknown, Peak#1 (161 mg, purity>99%based on HPLC, ee>99%) was randomly assigned as the R-isomer, and Peak#2(333 mg, purity >99% based on HPLC, ee>99%) was randomly assigned as theS-isomer (solvent residue presented this fraction was later confirmed bythe recovery yield from next step).

Step 2:9-((R)-1-(5-trifluoromethyl-6-(cis-4-(trifluoromethyl)cyclohexyloxy)-naphthalen-2-yl)-ethyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid

9-((R)-1-(5-trifluoromethyl-6-(cis-4-(trifluoromethyl)cyclohexyloxy)-naphthalen-2-yl)-ethyl)-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid methyl ester (161 mg, 0.282 mmol, the chiral center was randomlyassigned as R-isomer) was dissolved in tetrahydrofuran (2.0 mL, 25 mmol)and methanol (0.5 mL, 10 mmol). 3.0 M of aqueous sodium hydroxide (1.0mL, 3.0 mmol) was then added. The reaction was heated in microwave at100° C. for 10 min. The reaction mixture was then neutralized with 2NHCl. The organic phase was separated, dried and concentrated. The crudewas purified by HPLC to give title product as a white powder (130 mg,TFA salt). LCMS: RT 1.51 min.; MH+ 558.0; 1H NMR (400 MHz, METHANOL-d4)δ 8.32 (d, J=9.04 Hz, 1H), 8.07-8.21 (m, 2H), 7.79 (d, J=9.29 Hz, 1H),7.61 (d, J=9.29 Hz, 1H), 4.97-5.27 (m, 2H), 4.20 (d, J=12.05 Hz, 1H),3.35-3.46 (m, 1H), 3.09-3.22 (m, 1H), 1.58-2.63 (m, 22H).

Example 909-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid Step 1:9-((S)-1-(5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyloxy)-naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid methyl ester

Racemic9-{1-[5-Trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-ethyl}-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid methyl ester (493 mg, 0.86 mmol) was sent for chiral separation (byLotus Separations). The methods: IC (2×15 cm), 25% methanol (0.1%DEA)/CO₂, 100 bar; 60 ml/min., 220 nM.; ini vol: 1 mL, 20 mg/mLmethanol. Two isomers were obtained after the chiral separation. Sincethe absolute stereo chemistry is unknown, Peak#1 (161 mg, purity>99%based on HPLC, ee>99%) was randomly assigned as the R-isomer, and Peak#2(333 mg, purity >99% based on HPLC, ee>99%) was randomly assigned as theS-isomer (solvent residue presented this fraction was later confirmed bythe recovery yield from next step).

Step 2:9-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)-oxy)-naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

9-{(S)-1-[5-Trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]ethyl}-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid methyl ester (333 mg, 0.582 mmol) chiral center was randomlyassigned as S-isomer, may have residual solvent) was dissolved intetrahydrofuran (2.0 mL) and methanol (1.0 mL). 3.0 M of aqueous sodiumhydroxide (2.0 mL, 6.0 mmol) was then added. The reaction was heated inmicrowave at 100° C. for 10 min. The reaction mixture was thenneutralized with 2N HCl. The organic phase was separated, dried andconcentrated. The crude was purified by HPLC to give desired product asa white powder (152 mg, TFA salt). LCMS: RT 1.51 min.; MH+ 558.0; 1H NMR(400 MHz, METHANOL-d4) δ 8.32 (d, J=9.29 Hz, 1H), 8.08-8.20 (m, 2H),7.79 (d, J=9.29 Hz, 1H), 7.61 (d, J=9.29 Hz, 1H), 4.97-5.28 (m, 2H),4.20 (d, J=11.80 Hz, 1H), 3.33-3.46 (m, 1H), 3.11-3.23 (m, 1H),1.58-2.63 (m, 22H).

Example 919-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]-nonane-3-carboxylicacid

Step 1:6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthaldehyde

The title compound was prepared according to the procedure described for5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthaldehydefrom trans-4-ethylcyclohexanol. ¹H NMR (400 MHz, CHLOROFORM-d) δ 10.13(s, 1H), 8.23-8.39 (m, 2H), 8.09 (d, J=9.04 Hz, 1H), 8.00 (dd, J=1.63,9.16 Hz, 1H), 7.39 (d, J=9.29 Hz, 1H), 4.86 (br. S., 1H), 2.02-2.18 (m,2H), 1.54-1.71 (m, 4H), 1.39-1.53 (m, 2H), 1.22-1.38 (m, 3H), 0.92 (t,J=7.15 Hz, 3H). ESI-MS (M+H)⁺: 351.0

Step 2:1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)ethanol

To a solution of6-(cis-4-Ethyl-cyclohexyloxy)-5-trifluoromethyl-naphthalene-2-carbaldehyde(0.90 g, 2.56 mmol) in dry tetrahydrofuran (20 mL, 200 mmol) at −78° C.(acetone/dry ice bath) under argon was dropwise added 1.4 M ofmethylmagnesium bromide in toluene/THF (mixture of 75/25 (2.7 mL, 3.8mmol) over 10 min. After stirred at −78° C. for 1 h, allowed thereaction to warm up a little before quenched with sat.ammonium chloride,extracted with ethyl acetate. The organic phase was separated, dried,filtered and concentrated. The crude was purified by ISCO columnchromatography (EtOAc/heptane gradient from 0/100 to 60/40) to givedesired product as a colorless oil (0.84 g). LC-MS: RT 2.23 min.; MH+not seen, only seen 349.1 (M−OH) and 389.0 (M+Na).

Step 3:6-(1-bromoethyl)-2-((cis-4-ethylcyclohexyl)oxy)-1-(trifluoromethyl)naphthalene

To a solution of1-[6-(cis-4-Ethyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-ethanol(0.84 g, 1.1 mmol) in tetrahydrofuran (5.0 mL, 62 mmol) was added 1.0 Mof phosphorus tribromide in methylene chloride (1.15 mL, 1.15 mmol). Themixture was stirred at RT for 5 min. The reaction was diluted with ethylacetate, washed with water. The organic layer was then dried andconcentrated to give the title product as colorless oil (0.70 g) whichwas used in the next step without further purifications. LCMS: RT 2.62min.; MH+ not observed. Only see 349.0 (M-Br).

Step 4:9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]-nonane-3-carboxylicacid

To a mixture of potassium carbonate (53.1 mg, 0.384 mmol) and9-Aza-bicyclo[3.3.1]-nonane-3-carboxylic acid methyl ester (99.8 mg,0.454 mmol) in N,N-dimethylformamide (3.0 mL, 39 mmol) was added asolution of6-(1-Bromo-ethyl)-2-(4-ethyl-cyclohexyloxy)-1-trifluoromethyl-naphthalene(0.15 g, 0.35 mmol) in DMF (5 ml). The reaction mixture was stirred atRT overnight. The mixture partitioned between ethyl acetate andsaturated sodium chloride. The organic phase was washed with brine,dried, filtered and concentrated. The crude was purified by HPLC to givemethyl9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylateas a white powder (LC-MS: RT 1.78 min., MH+ 532.1) which was thendissolved in tetrahydrofuran (2.0 mL, 25 mmol) and methanol (1.0 mL, 25mmol). 3.0 M of aqueous sodium hydroxide (1.0 mL, 3.0 mmol) was added,and the reaction mixture was heated in microwave at 100° C. for 10 min.Ethyl acetate was added, the mixture was neutralized with 2N HCl (aq).The organic layer was separated, dried and concentrated. The crude wasthen purified by HPLC to give the titled product as a white powder (52mg, TFA salt). LC-MS: RT 1.67 min., MH+ 518.1; 1H NMR (400 MHz,METHANOL-d4) δ 8.30 (d, J=9.04 Hz, 1H), 8.04-8.19 (m, 2H), 7.77 (d,J=9.29 Hz, 1H), 7.58 (d, J=9.29 Hz, 1H), 5.00-5.28 (m, 1H), 4.95 (br.S., 1H), 4.20 (d, J=12.05 Hz, 1H), 3.38 (dd, J=6.02, 11.80 Hz, 1H), 3.17(d, J=14.31 Hz, 1H), 2.29-2.62 (m, 3H), 1.52-2.28 (m, 16H), 1.23-1.51(m, 5H), 0.93 (t, J=7.15 Hz, 3H).

Example 929-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1:1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)-propan-1-ol

To a solution of6-(4-ethyl-cyclohexyloxy)-5-trifluoromethyl-naphthalene-2-carbaldehyde(1.0 g, 2.8 mmol) in dry tetrahydrofuran (20 mL, 200 mmol) at −78° C.(acetone/dry ice bath) under argon was dropwise added 3.0 M ofethylmagnesium bromide in ether (1.05 mL, 3.14 mmol). After stirred at−78° C. for 2 h, the reaction was allowed to warm up a little beforequenched with sat.ammonium chloride, the product was extracted withethyl acetate. The organic phase was separated, dried, filtered andconcentrated. The crude was purified by ISCO column chromatography(ethyl acetate/heptane gradient from 0/100 to 60/40) to give desiredproduct as a colorless oil (0.60 g). LC-MS: RT 2.37 min.; MH+ notobserved, only seen 363.0 (M-OH) and 403 (M+Na).

Step 2:6-(1-bromopropyl)-2-((cis-4-ethylcyclohexyl)oxy)-1-(trifluoromethyl)-naphthalene

The title compound was prepared according to the procedure described forcompound6-(1-bromoethyl)-2-((cis-4-ethylcyclohexyl)oxy)-1-(trifluoromethyl)naphthalene. The compound was used in the next steps without furtherpurifications. Step 3:9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

To a mixture of potassium carbonate (71.7 mg, 0.52 mmol) and9-Aza-bicyclo[3.3.1]-nonane-3-carboxylic acid methyl ester hydrochloride(59.5 mg, 0.27 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) wasadded a solution of6-(1-Bromo-propyl)-2-(4-ethyl-cyclohexyloxy)-1-trifluoromethyl-naphthalene(0.10 g, 0.22 mmol) in DMF (5 ml). The reaction mixture was stirred atRT overnight. LCMS showed formation of the desired ester, methyl9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate(RT 1.84 min., MH+ 546.1). The mixture partitioned between ethyl acetateand water. The organic phase was washed with brine, dried, filtered andconcentrated. The crude was purified by HPLC to give desiredintermediate as a colorless oil which was then dissolved intetrahydrofuran (1.0 mL, 12 mmol) and methanol (0.5 mL, 10 mmol),treated with 3.0 M of aqueous sodium hydroxide (1.0 mL, 3.0 mmol). Thereaction was heated in microwave at 100° C. for 10 min. Cooled down, thereaction was neutralized with 2N HCl. The organic phase was thenseparated, dried and concentrated. The crude was purified by HPLC togive the title product as a white powder (6 mg, TFA salt). LC-MS: RT1.74 min., MH+ 532.1; 1H NMR (400 MHz, METHANOL-d4) δ 8.32 (d, J=7.53Hz, 1H), 8.12 (d, J=9.29 Hz, 2H), 7.74 (d, J=8.28 Hz, 1H), 7.59 (d,J=9.29 Hz, 1H), 4.89-5.01 (m, 2H), 4.24 (br. S., 1H), 3.35-3.45 (m, 1H),3.05-3.23 (m, 1H), 1.82-2.61 (m, 13H), 1.52-1.80 (m, 5H), 1.23-1.52 (m,5H), 0.93 (t, J=7.15 Hz, 3H), 0.76 (t, J=7.28 Hz, 3H).

Example 939-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1:6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthaldehyde

The titled compound was prepared according to the procedure describedfor5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthaldehydefrom trans-4-methylcyclohexan-1-ol. ¹H NMR (400 MHz, CDCl₃) δ 10.11 (s,1H), 8.31 (d, J=8.8 Hz, 1H), 8.26 (d, J=1.2 Hz, 1H), 8.07 (d, J=9.2 Hz,1H), 7.98 (dd, J=1.6 Hz, 9.2 Hz, 1H), 7.37 (d, J=9.2 Hz, 1H), 4.84 (s,1H), 2.09-2.06 (m, 2H), 1.68-1.62 (m, 2H), 1.54-1.43 (m, 5H), 0.96 (d,J=5.2 Hz, 3H); ESI-MS (M+H)⁺: 336.9

Step 2:1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)ethanol

To a solution of6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthaldehyde(673 mg, 2.00 mmol) in dry THF (10 mL) at −78° C. (acetone/dry ice bath)under N₂ was added a solution of 1.4M MeMgBr in toluene/THF (2.14 mL,3.00 mmol). After stirred at −78° C. for 40 min, it was switched to anice-cold bath, and stirred at 0° C. for 30 min. The reaction wasquenched with satd.NH₄Cl, extracted with EtOAc. The organic phase wasdried, filtered and concentrated. The residue was purified by flashchromatography on silica gel column to provide the alcohol as acolorless oil (580 mg, yield 82%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.14 (d,J=9.06 Hz, 1H), 8.01 (d, J=7.18 Hz, 1H), 7.88 (s, 1H), 7.62 (dd, J=1.89,9.06 Hz, 1H), 7.56 (d, J=9.44 Hz, 1H), 5.30 (d, J=4.15 Hz, 1H), 4.95(br. S., 1H), 4.80-4.91 (m, 1H), 1.85-1.96 (m, 2H), 1.62 (t, J=13.22 Hz,2H), 1.37 (d, J=12.46 Hz, 3H), 1.22-1.53 (m, 5H), 0.90 (d, J=6.04 Hz,3H); LCMS m/z 335.2 [M+H−H₂O]⁺

Step 3:6-(1-Bromoethyl)-2-((cis-4-methylcyclohexyl)oxy)-1-(trifluoromethyl)naphthalene

To a solution of1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)ethanol(528 mg, 1.50 mmol) in THF under N₂ was added 1 M of PBr₃ in methylenechloride at room temperature. The reaction mixture was stirred at rt for5 minutes, and then partitioned between EtOAc and water. The organicphase was dried, filtered and concentrated to get the bromideintermediate as a colorless oil. The oil product was dissolved in DMF(15 mL) to make a 0.1M solution, and used as such for next stepdirectly.

Step 4: methyl9-(1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate

To a solution of 0.1M6-(1-bromoethyl)-2-((cis-4-methylcyclohexyl)oxy)-1-(trifluoromethyl)naphthalenein DMF (8 mL, 0.8 mmol) was added9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid methyl ester; HCl salt (228mg, 1.04 mmol) and K₂CO₃ (166 mg, 1.20 mmol). The reaction mixture wasstirred at rt overnight. It was partitioned between EtOAc and brine. Theorganic phase was dried over MgSO₄, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel column to getthe desired ester as a colorless oil (235 mg, yield 57%). LCMS m/z 518.3[M+H]⁺

Step 5:9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

To a solution of above ester (235 mg, 0.454 mmol) in THF (1 mL) and MeOH(1 mL) was added 3 M of NaOH in water (0.3 mL, 0.9 mmol). The reactionmixture was heated with microwave irritation at 100° C. for 10 min.Neutralized with 1N HCl and purified by HPLC (TFA method) to collect thedesired acid as a white powder after lyophilization (223 mg, yield 80%).¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (d, J=9.29 Hz, 1H), 8.02 (d, J=7.53 Hz,1H), 7.87 (s, 1H), 7.65 (d, J=9.04 Hz, 1H), 7.56 (d, J=9.29 Hz, 1H),4.96 (br. S., 1H), 4.18 (q, J=6.19 Hz, 1H), 2.87-3.14 (m, 3H), 1.14-2.13(m, 22H), 0.90 (d, J=6.27 Hz, 3H); LCMS m/z 504.3 [M+H]⁺

Example 949-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid, enantiomer 1

Racemic9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid was subjected to preparative SFC by the following method: AS-H(2×15 cm); 15% ethanol (0.1% DEA)/CO₂, 100 bar; 70 mL/min, 220 nm; Injvol.: 0.5 mL, 20 mg/mL ethanol. Enantiomer 1: ¹H NMR (400 MHz,METHANOL-d₄) δ 8.30 (d, J=8.78 Hz, 1H), 8.11 (br. S., 2H), 7.77 (d,J=8.28 Hz, 1H), 7.58 (d, J=9.29 Hz, 1H), 5.00-5.28 (m, 1H), 4.94 (br.S., 1H), 4.18 (br. S., 1H), 3.36-3.46 (m, 1H), 3.06-3.23 (m, 1H),1.82-2.64 (m, 11H), 1.78 (d, J=6.78 Hz, 3H), 1.69 (t, J=13.30 Hz, 3H),1.33-1.58 (m, 5H), 0.95 (d, J=5.77 Hz, 3H); LCMS m/z 504.3 [M+H]⁺

Example 959-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid, enantiomer 2

Racemic9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid was subjected to preparative SFC by the following method: AS-H(2×15 cm); 15% ethanol (0.1% DEA)/CO₂, 100 bar; 70 mL/min, 220 nm; Injvol.: 0.5 mL, 20 mg/mL ethanol. Enantiomer 2: ¹H NMR (400 MHz,METHANOL-d₄) δ 8.30 (d, J=8.78 Hz, 1H), 8.11 (br. S., 2H), 7.77 (d,J=9.04 Hz, 1H), 7.58 (d, J=9.29 Hz, 1H), 5.00-5.27 (m, 1H), 4.94 (br.S., 1H), 4.18 (br. S., 1H), 3.36-3.46 (m, 1H), 3.06-3.22 (m, 1H),1.82-2.65 (m, 11H), 1.78 (d, J=6.53 Hz, 3H), 1.62-1.74 (m, 3H),1.32-1.59 (m, 5H), 0.95 (d, J=5.77 Hz, 3H); LCMS m/z 504.3 [M+H]⁺

Example 968-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

Step 1:(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methanol

To a mixture of6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthaldehyde(1.34 g, 4.00 mmol) in methanol (20 mL) was added NaBH₄ (152 mg, 4.02mmol), and stirred at rt for 30 min, LCMS shows the reaction wascompleted. Concentrated to remove most of the solvent, added water andextracted with ethyl acetate. The organic phase was dried, filtered andconcentrated. The residue was purified by flash chromatography on silicagel column to give desired product as a white solid. (1.34 g, yield99%). ¹H NMR (300 MHz, METHANOL-d₄) δ 8.14 (dd, J=1.51, 9.06 Hz, 1H),8.04 (d, J=9.44 Hz, 1H), 7.83 (s, 1H), 7.56 (dd, J=1.89, 9.06 Hz, 1H),7.46 (d, J=9.06 Hz, 1H), 4.88 (br. S., 1H), 4.76 (s, 2H), 1.99-2.13 (m,2H), 1.61-1.78 (m, 2H), 1.43-1.58 (m, 5H), 0.97 (d, J=5.67 Hz, 3H); LCMSm/z 321.1 [M+H−H₂O]⁺

Step 2:8-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was synthesized according to the procedure describedin Example 93, Steps 3-5 from(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methanoland methyl 8-azabicyclo[3.2.1]octane-3-carboxylate (total yield 61% forthree steps). ¹H NMR (300 MHz, METHANOL-d₄) δ 8.29 (d, J=7.93 Hz, 1H),8.15 (d, J=9.44 Hz, 1H), 8.08 (s, 1H), 7.72 (dd, J=1.89, 9.06 Hz, 1H),7.60 (d, J=9.06 Hz, 1H), 4.96 (br. S., 1H), 4.38 (br. S., 2H), 4.04 (br.S., 2H), 2.99 (quin, J=8.97 Hz, 1H), 2.51 (br. S., 2H), 2.04-2.23 (m,8H), 1.72 (t, J=13.03 Hz, 2H), 1.39-1.59 (m, 5H), 0.97 (d, J=5.29 Hz,3H); LCMS m/z 476.2 [M+H]⁺

Example 979-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

To a mixture of6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthaldehyde (17mg, 0.050 mmol), 9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid methylester; HCl salt (15 mg, 0.068 mmol) and sodium triacetoxyborohydride (17mg, 0.080 mmol) in THF (0.6 mL) was added acetic acid (5.7 uL, 0.10mmol). The reaction mixture was heated with microwave irritation at 100°C. for 20 min. To the above mixture was added MeOH (0.4 mL) and 3 M ofNaOH (0.20 mL, 0.60 mmol), and heated with microwave irritation at 100°C. for 10 min. LC-MS shows the hydrolysis was completed. Neutralizedwith 1N HCl, and purified by HPLC (TFA method) to provide the desiredproduct as a white powder after lyophilization (13 mg, 43%). ¹H NMR (400MHz, DMSO-d₆) δ 8.09-8.28 (m, 3H), 7.82 (d, J=9.29 Hz, 1H), 7.68 (d,J=9.54 Hz, 1H), 5.02 (br. S., 1H), 4.44-4.75 (m, 2H), 3.42-3.64 (m, 2H),3.23 (td, J=6.27, 12.55 Hz, 1H), 1.13-2.46 (m, 19H), 0.90 (d, J=6.02 Hz,3H); LCMS m/z 490.3 [M+H]⁺.

Example 989-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1:6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthaldehyde

A solution of6-(4,4-Difluoro-cyclohexyloxy)-5-iodo-naphthalene-2-carbaldehyde (3.0 g,7.2 mmol), hexamethylphosphoramide (6.02 mL, 34.3 mmol) inN,N-dimethylformamide (30 mL, 400 mmol) was degassed with argon. To thiswas added copper(I) iodide (2.34 g, 12.3 mmol) and methylfluorosulphonyldifluoroacetate (4.49 mL, 34.3 mmol) and the reaction wasstirred at 85° C. under an atmosphere of argon. After stirring for 3hours, LCMS showed no starting material left and confirms the identityof the product (RT=2.01 min, MH+ 359.10). The reaction was diluted withEtOAc, filtered off the solid, and the filtrate was washed with brine,and water. The organic layer was then separated, dried, concentrated.The crude was recrystallized from methanol to give the title product asa white powder (1.95 g). LCMS: RT 2.01 min; MH+ 359.1; 1H NMR (400 MHz,CHLOROFORM-d) δ 10.15 (s, 1H), 8.28-8.40 (m, 2H), 8.14 (d, J=9.29 Hz,1H), 8.03 (dd, J=1.63, 9.16 Hz, 1H), 7.40 (d, J=9.04 Hz, 1H), 4.86 (br.S., 1H), 2.11-2.37 (m, 4H), 1.93-2.08 (m, 4H).

Step 2:9-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

A mixture of 9-Aza-bicyclo[3.3.1]nonane-3-carboxylic acid methyl esterhydrochloride (74 mg, 0.33 mmol) and triethylamine (0.04 mL, 0.27 mmol)in 1,2-dichloroethane (2 mL) was stirred at RT for 20 min.6-(4,4-difluoro-cyclohexyloxy)-5-trifluoromethyl-naphthalene-2-carbaldehyde(80.0 mg, 0.22 mmol) was then added. The reaction was then stirred at50° C. for 1 h, cooled down, sodium triacetoxyborohydride (76 mg, 0.36mmol) was added, and the reaction was stirred at rt for overnight. LCMSshowed desired ester intermediate (RT 1.46 min.; MH+ 526.2). Worked upwith ethyl acetate and brine, dried over magnesium sulfate, filtered andconcentrated. The crude was then dissolved in tetrahydrofuran (1 mL),1.0 M of aqueous lithium hydroxide (2 mL) was added. The mixture wasstirred at RT for 3 h. Neutralized with cone. HCl, the product wasextracted with ethyl acetate. The organic layer was concentrated. Thecrude was purified by HPLC to give the desired product as a white powder(49 mg, TFA salt). LCMS: RT 1.37 min.; MH+ 512.2; 1H NMR (400 MHz,METHANOL-d4) δ 8.28 (d, J=9.04 Hz, 1H), 8.11-8.21 (m, 2H), 7.76 (dd,J=1.25, 9.04 Hz, 1H), 7.64 (d, J=9.29 Hz, 1H), 4.97 (br. S., 1H),4.62-4.79 (m, 2H), 3.65 (d, J=12.55 Hz, 2H), 3.35-3.53 (m, 1H),2.44-2.69 (m, 2H), 1.64-2.38 (m, 16H).

Example 998-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

Step 1: 2-bromo-6-((cis-4-methylcyclohexyl)oxy)naphthalene

To a mixture of trans-4-methylcyclohexan-1-ol (20.5 g, 179.6 mmol, 1.2eq) and 6-bromonaphthalen-2-ol (33.1 g, 149.8 mmol) in THF (300 mL) wasadded PPh₃ (62.8 g, 239.5 mmol, 1.6 eq), followed by DIAD (48.4 g, 239.5mmol, 1.6 eq) dropwise. The mixture was stirred at rt for 24 h andconcentrated. The residue was diluted with EtOAc (300 mL), washed withwater (100 mL) and brine (100 mL). The organic layer was dried overanhydrous Na₂SO₄ and evaporated. The residue was purified by columnchromatography on silica gel (Petroleum ether/EtOAc=20/1) to give2-bromo-6-((cis-4-methylcyclohexyl)oxy)naphthalene as a white solid(35.5 g, yield: 75%).

Step 2: 6-bromo-2-((cis-4-methylcyclohexyl)oxy)-1-naphthaldehyde

To a solution of 2-bromo-6-((cis-4-methylcyclohexyl)oxy)naphthalene(35.5 g, 111.6 mmol) in CH₂Cl₂ (350 mL) was added a solution of TiCl₄(31.5 g, 167.5 mmol, 1.5 eq) and dichloro(methoxy)methane (14.0 g, 122.8mmol, 1.1 eq) in CH₂Cl₂ (700 mL) at 0° C. After addition, the mixturewas stirred at rt for 12 h. 1N HCl (200 mL) was added and the mixturewas extracted with CH₂Cl₂ (500 mL×2). The organic layers were dried overNa₂SO₄, filtered and concentrated to give6-bromo-2-((cis-4-methylcyclohexyl)oxy)-1-naphthaldehyde as a lightyellow solid (38.0 g, yield: 98%), which was used to the next stepwithout further purification.

Step 3:6-bromo-1-(difluoromethyl)-2-((cis-4-methylcyclohexyl)oxy)naphthalene

To a solution of6-bromo-2-((cis-4-methylcyclohexyl)oxy)-1-naphthaldehyde (38.0 g, 109.83mmol) in DCE (200 mL) was added DAST (106.1 g, 658.98 mmol, 6.0 eq) atrt. The mixture was stirred at 80° C. for 24 h and cooled down. Water(300 mL) was added and the mixture was extracted with CH₂Cl₂ (200 mL×2).The combined organic layers were washed with sat. aq. NaHCO₃ (200 mL),dried over Na₂SO₄, filtered and concentrated. The residue was washedwith heptane to give6-bromo-1-(difluoromethyl)-2-((cis-4-methylcyclohexyl)oxy)naphthalene asa white solid (38.0 g, yield: 95%). ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d,J=9.2 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.58 (dd,J=2.0 Hz, 9.2 Hz, 1H), 7.56 (t, J=54.8 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H),4.72-4.70 (m, 1H), 2.04-2.00 (m, 2H), 1.63-1.54 (m, 5H), 1.35 (m, 2H),0.96 (d, J=6.4 Hz, 3H).

Step 4:5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)-2-naphthaldehyde

To a solution of6-bromo-1-(difluoromethyl)-2-((cis-4-methylcyclohexyl)oxy)naphthalene(17 g, 46.19 mmol) in THF (130 mL) was added ^(n)BuLi (33 mL, 1.6 M,55.43 mmol, 1.2 eq) dropwise at −78° C. After addition, the mixture wasstirred at −78° C. for 30 min. DMF (6.74 g, 92.38 mmol, 2.0 eq) wasadded to the mixture and stirring continued for 2 hours −78° C. and thereaction was quenched with water (200 mL) and extracted with CH₂Cl₂ (200mL×2). The combined organic layers were washed with water (200 mL×2),brine (200 mL×2) and concentrated. The residue was washed with heptaneto give5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)-2-naphthaldehyde as awhite solid (12.5 g, yield: 85%). ¹H NMR (400 MHz, CDCl₃) δ 10.12 (s,1H), 8.46 (d, J=8.8 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.03 (d, J=9.2 Hz,1H), 7.99 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.59 (t, J=54.8 Hz, 1H), 7.32 (d,J=8.8 Hz, 1H), 4.80-4.78 (m, 1H), 2.07-2.03 (m, 2H), 1.67-1.55 (m, 5H)1.37-1.33 (m, 2H) 0.97 (d, J=6.4 Hz, 3H). ESI-MS (M+H)⁺: 319.1.

Step 5: Methyl8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalene-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylate

To a mixture of potassium carbonate (62 mg, 0.45 mmol) and8-aza-bicyclo[3.2.1]octane-3-carboxylic acid methyl ester HCl salt (80mg, 0.39 mmol) was added a solution of6-(1-bromopropyl)-1-(difluoromethyl)-2-((cis-4-methylcyclohexyl)oxy)naphthalenein DMF (3 mL, 0.3 mmol). The reaction mixture was stirred at roomtemperature overnight. The mixture was filtered, and purified by HPLC(TFA method) to collect the desired ester as a white powder afterlyophilization (81 mg, yield 44%). LCMS m/z 500.1 [M+H]

Step 6:8-(1-(5-(Difluoromethyl)-6-((cis-4-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

To the above ester in THF (0.6 mL) and MeOH (0.6 mL) was added 3 M ofNaOH in water (0.200 mL, 0.600 mmol). The reaction mixture was heated at55° C. (hot plate) for 1 h. Neutralized with 2N HCl, diluted with MeOH,and purified by HPLC (TFA method) to collect TFA salt of the the desiredacid as a white powder after lyophilization (67 mg, yield 84%). ¹H NMR(400 MHz, METHANOL-d₄) δ 8.45 (d, J=8.78 Hz, 1H), 8.05 (d, J=9.29 Hz,1H), 7.99 (s, 1H), 7.40-7.78 (m, 3H), 4.89 (br. S., 1H), 4.51-4.65 (m,1H), 4.07 (dd, J=3.26, 11.55 Hz, 1H), 3.37-3.50 (m, 1H), 2.86-3.05 (m,1H), 2.49-2.64 (m, 1H), 2.35-2.48 (m, 1H), 1.86-2.33 (m, 10H), 1.65-1.80(m, 2H), 1.46-1.63 (m, 3H), 1.27-1.42 (m, 2H), 0.98 (d, J=6.27 Hz, 3H),0.79 (t, J=7.28 Hz, 3H); LCMS m/z 486.1 [M+H]⁺

Example 1009-((5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1:5-(difluoromethyl)-6-((cis-4-trifluoromethylcyclohexyl)oxy)-2-naphthaldehyde

The title compound was prepared using the method described for compound5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)-2-naphthaldehyde from6-bromonaphthalen-2-ol andtrans-4-trifluoromethylcyclohexane-1-mesylate. ESI-MS (M+H)⁺: 373.2

Step 2:9-((5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

A mixture of5-(difluoromethyl)-6-((cis-4-trifluoromethylcyclohexyl)oxy)-2-naphthaldehyde(60 mg, 0.161 mmol, 1.0 eq), methyl9-azabicyclo[3.3.1]nonane-3-carboxylate, HCl salt (32 mg, 0.177 mmol,1.1 eq) and Titanium (IV) isopropoxide (92 mg, 0.323 mmol, 2.0 eq) inTHF (3 mL) was stirred at 100° C. for 1 h and cooled to rt. NaBH(Oac)₃(68 mg, 0.323 mmol, 2.0 eq) was added and the mixture was stirred at100° C. for 1 h. Water (30 mL) was added and the mixture was extractedwith CH₂Cl₂ (30 mL×2). The combined organic layers were washed withwater (60 mL×2) and concentrated. The residue was purified by columnchromatography on silica gel (PE/EA=6:1) to give the desired ester,methyl9-((5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylateas a colorless solid (30 mg, yield: 34%). ESI-MS (M+H)⁺: 540.1. Theabove ester was then converted to the title compound with the yield:60%. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.54 (br s, 1H), 8.27 (d, J=8.8 Hz,1H), 8.18 (s, 1H), 8.15 (d, J=9.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.64(d, J=9.2 Hz, 1H), 7.63 (t, J=54.4 Hz, 1H), 5.04 (s, 1H), 4.69-4.61 (m,2H), 3.55-3.51 (m, 2H), 3.27-3.21 (m, 1H), 2.47-2.40 (m, 3H), 2.21-1.93(m, 8H), 1.76-1.56 (m, 8H). ESI-MS (M+H)⁺: 526.3.

Example 1019-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1: 2-Methylquinolin-6-ol

To a solution of 6-methoxy-2-methylquinoline (prepared according to theprocedure described in reference: Kitamura et al, J. Syn. Org. Chem.2003 (15), 2415, which is incorporated by reference in its entirety) (10g, 57.5 mmol) in 150 mL of dichloromethane was dropwise added a solutionof BBr₃ (43.1 g, 172.5 mmol) in dichloromethane (100 mL) at −78° C. Themixture was allowed to warm to RT and stirred at RT for 16 h. Thereaction was carefully quenched with methanol at 0° C. and the mixturewas diluted with saturated aqueous sodium bicarbonate. The aqueousmixture was extracted with ethyl acetate (3×). The combined organicswere dried, filtered, and concentrated to give the title compound as ayellow solid (7.2 g). ¹H NMR (CDCl₃, 300 MHz) δ: 7.87-7.81 (m, 2H),7.20-7.08 (m, 3H), 2.65 (s, 3H).

Step 2: 5-Iodo-2-methylquinolin-6-ol

To a solution of 2-methylquinolin-6-ol (4.1 g, 27.3 mmol) indichloromethane (200 mL) was added N-iodosuccinamide (9.2 g, 40.9 mmol)and trifluroacetic acid (1.9 g, 8.2 mmol). The mixture was stirred atroom temperature for 16 h. The mixture was basified with ammonia topH=7.5, and washed with 100 mL of water. The organic layer was dried andconcentrated. The crude was purified by column chromatography on silicagel (petroleum ether/ethyl acetate 8/1) to give the title compound as ayellow solid (4.5 g). ¹H NMR (DMSO-d6, 300 MHz) δ 10.76 (s, 1H), 8.16(d, J=8.7 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 7.40(d, J=8.7 Hz, 1H), 2.62 (s, 3H).

Step 3:5-Iodo-2-methyl-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinoline

The mixture of 5-iodo-2-methylquinolin-6-ol (8.0 g, 28 mmol),trans-4-(tert-butyl)cyclohexyl methanesulfonate (6.9 g, 28 mmol, 1.0 eq)and cesium carbonate (9.2 g, 28 mmol) in tert-butanol (100 mL) washeated at 90° C. for 6 h. The mixture was cooled down and filtered. Thefiltrate was concentrated and the residue was purified by columnchromatography on silica gel (petroleum ether/ethyl acetate 20/1) togive the title compound as a white solid (4.9 g). ¹H NMR (400 MHz,CDCl₃) δ 8.32 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.36 (d, J=9.2Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 4.86 (s, 1H), 2.74 (s, 3H), 2.23-2.19(m, 2H), 2.17-2.01 (m, 3H), 1.81-1.78 (m, 2H), 1.63-1.57 (m, 2H); ESI-MS(M+H)⁺: 436.1.

Step 4:2-Methyl-5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinoline

The title compound was synthesized using the same procedure describedfor compound5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthaldehydefrom 5-iodo-2-methyl-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolineto give the title compound as a white solid (40% yield). ¹H NMR (400MHz, CDCl₃) δ 8.45 (d, J=8.4 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.48 (d,J=9.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 4.86 (s, 1H), 2.73 (s, 3H),2.25-2.21 (m, 2H), 2.14-2.11 (m, 1H), 1.89-1.78 (m, 4H), 1.68-1.58 (m,2H); ESI-MS (M+H)⁺: 378.1.

Step 5:5-(Trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinoline-2-carbaldehyde

To a solution of2-methyl-5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinoline(1 eq.) in dioxane was added SeO₂ (2.5 eq.). The mixture was stirred at100° C. for 1.5 h and concentrated. The residue was purified by columnchromatography on silica gel with heptane and ethyl acetate to give thetitled compound as a yellow solid (yield: 36%). 1H NMR (400 MHz, CDCl₃)δ 10.18 (s, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.39 (d, J=9.6 Hz, 1H), 8.08(d, J=9.6 Hz, 1H), 7.62 (d, J=9.6 Hz, 1H), 4.96 (s, 1H), 2.28-2.24 (m,2H), 2.19-2.10 (m, 1H), 1.93-1.81 (m, 4H), 1.73-1.65 (m, 2H); ESI-MS(M+H)⁺: 392.0.

Step 6:9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

A mixture of 9-Aza-bicyclo[3.3.1]nonane-3-carboxylic acid methyl ester;HCl salt (67 mg, 0.31 mmol) and triethylamine (0.05 mL, 0.33 mmol) in1,2-dichloroethane (2.0 mL) was stirred at RT for 20 min.5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)-cyclohexyl)oxy)quinoline-2-carbaldehyde(80.0 mg, 0.20 mmol) was then added. The reaction was then stirred at50° C. for 1 h, cooled down, sodium triacetoxy-borohydride (86.7 mg,0.41 mmol) was added, and the reaction was stirred at RT overnight. LCMSshowed desired intermediate (RT 1.50 min.; MH+ 559.3). Worked up withethyl acetate and brine, dried over magnesium sulfate and concentrated.The crude was then dissolved in tetrahydrofuran (2.0 mL). 2.0 mL of 1.0M Lithium hydroxide in Water was added. The mixture was stirred at RTfor 3 h, then neutralized with conc. HCl, extracted with ethyl acetate.The organic layer was concentrated, and purified by HPLC to give thedesired product as a white powder (35 mg). LCMS: RT 1.43 min.; MH+545.2; ¹H NMR (400 MHz, METHANOL-d4) δ 8.59 (d, J=9.04 Hz, 1H), 8.23 (d,J=9.54 Hz, 1H), 7.75 (d, J=9.54 Hz, 1H), 7.54 (d, J=9.04 Hz, 1H), 4.97(br. S., 1H), 4.80-4.87 (m, 2H), 3.78 (br. S., 2H), 3.26-3.41 (m, 1H),1.56-2.49 (m, 19H).

Example 1028-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

Step 1:1-(5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyl)oxy)-quinolin-2-yl)ethanol

To a solution of5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-quinoline-2-carbaldehyde(200.0 mg, 0.51 mmol) in dry tetrahydrofuran (4.0 mL, 49 mmol) at −78°C. under argon was dropwise added 1.4 M of methyl bromide in toluene/THF(solvent mixture, 75/25) (0.5476 mL, 0.7667 mmol). After stirred at −78°C. for 2 h, allowed the reaction to warm up a little before quenchedwith saturated ammonium chloride, extracted with ethyl acetate. Theorganic phase was dried, filtered and concentrated. The crude waspurified by ISCO EtOAc/heptane gradient from 0/100 to 100/0) to give thetitle product as a colorless oil (133 mg). LC-MS: RT 1.53 min.; MH+408.0.

Step 2:1-(5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyl)-oxy)quinolin-2-yl)ethanone

To a solution of1-[5-Trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-quinolin-2-yl]-ethanol(0.13 g, 0.32 mmol) in acetonitrile (2.00 mL, 38.3 mmol) was addedDess-Martin periodinane (0.271 g, 0.638 mmol). After stirred at RTovernight, the reaction was diluted with ethyl acetate, washed withaqueous Na₂S203/NaHCO₃ (1:1), followed by water, and brine. The organicphase was dried, filtered and concentrated to give the desired productas a white powder (127 mg) which was used in the next step withoutfurther purifications. LC-MS: RT 2.16 min.; MH+ 405.9;

Step 3:8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

To a mixture of1-[5-Trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-quinolin-2-yl]-ethanone(40.0 mg, 0.0987 mmol) and 8-Aza-bicyclo[3.2.1]octane-3-carboxylic acidmethyl ester; HCl salt (30.45 mg, 0.1480 mmol) in Tetrahydrofuran (2.0mL, 24 mmol) was added Acetic acid (11.22 uL, 0.1974 mmol), Titaniumtetraisopropoxide (33.66 mg, 0.1184 mmol) and Sodiumtriacetoxyborohydride (41.83 mg, 0.1974 mmol), and the reaction washeated in microwave at 100° C. for 10 min. LCMS showed desired ester (RT1.53 min, MH+ 559.0) with 40% conversion, added one more eq of B andNa(OAc)₃BH, heated in microwave at 100° C. for another 10 min.conversion improved to 50%, repeated one more time, conversion ˜60%.Worked up with EtOAc and water. The organic layer was dried over MgSO₄and concentrated. The crude was re-dissolved in tetrahydrofuran (1.0 mL,12 mmol) and methanol (1.0 mL, 25 mmol), treated with 3.0 M of sodiumhydroxide in water (1.0 mL, 3.0 mmol), heated in microwave at 100° C.for 10 min., acidified with 2N HCl, the organic phase was dried andconcentrated. The crude was purified by HPLC to give the desired productas a white powder (7 mg, bis-TFA salt). LCMS: RT 1.46 min.; MH+ 545.0;1H NMR (400 MHz, METHANOL-d4) δ 8.72 (d, J=9.04 Hz, 1H), 8.37 (d, J=9.54Hz, 1H), 7.88 (d, J=9.54 Hz, 1H), 7.68 (d, J=9.04 Hz, 1H), 5.10 (br. S.,1H), 4.71 (q, J=6.53 Hz, 1H), 4.52 (d, J=6.02 Hz, 1H), 3.74 (d, J=2.76Hz, 1H), 2.93-3.10 (m, 1H), 1.93-2.62 (m, 11H), 1.68-1.91 (m, 9H);

Example 1039-((6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

Step 1: methyl 6-((trans,trans)-3,5-dimethylcyclohexyl)oxy)-2-naphthoate

To a mixture of 6-hydroxy-naphthalene-2-carboxylic acid methyl ester(1.00 g, 4.94 mmol), (cis,cis,cis)-3,5-dimethyl-cyclohexanol (0.6341 g,4.945 mmol) and triphenylphosphine (2.354 g, 8.977 mmol) in toluene (20mL, 200 mmol) was stirred for 20 min, then, diisopropyl azodicarboxylate(1.1 mL, 5.4 mmol) was added drop wise at 0° C. The mixture becameclear. The solution was stirred at reflux overnight. Afterconcentration, the residue was purified with silica gel eluted withEtOAc in hexanes from 0 to 20% to give methyl6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-2-naphthoate as a whiteprecipitate (247 mg, 16%). LCMS showed Rt=2.39 min, a M+H peak atm/z=313.20.

Step 2: methyl6-((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-iodo-2-naphthoate

A mixture of methyl6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-2-naphthoate (247 mg,0.000791 mol), N-iodosuccinimide (199 mg, 0.000886 mol) and zirconiumtetrachloride (28 mg, 0.00012 mol) in methylene chloride (5.07 mL,0.0791 mol) was heated to reflux under Ar in a vial for 2 h. Theprecipitate was filtered off and the residue was purified with silicagel column eluted with EtOAc in hex from 0 to 40% to give methyl6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-iodo-2-naphthoate as asolid (130 mg, 38%). LCMS: Rt=2.59 min, m/z=439.10 [M+1]. ¹H NMR (400MHz, CHLOROFORM-d) δ 8.49 (s, 1H), 8.12-8.21 (m, 1H), 8.02-8.10 (m, 1H),7.87 (d, J=8.91 Hz, 1H), 7.22 (d, J=9.10 Hz, 1H), 4.31-4.51 (m, 1H),3.98 (s, 3H), 2.16 (d, J=12.49 Hz, 2H), 1.13-1.76 (m, 8H), 0.91-1.03 (m,6H), 0.57-0.75 (m, 1H).

Step 3: methyl 6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoate

To a solution of methyl6-((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-iodo-2-naphthoate (130mg, 0.30 mmol), hexamethylphosphoramide (0.26 mL, 1.5 mmol) andcopper(I) iodide (85 mg, 0.44 mmol) in N,N-dimethylformamide (2 mL, 20mmol) was added methyl fluorosulphonyldifluoroacetate (0.19 mL, 1.5mmol). The mixture was heated at 80° C. overnight. LCMS showed desiredproduct peak, Rt=2.49 min, m/z=381.10 ([M+1], 100%). The solvent wasevaporated and C/C with EA/HE gave the product methyl6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoate(106 mg, 94%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.54 (s, 1H), 8.25 (d,J=9.22 Hz, 1H), 8.11 (d, J=11.11 Hz, 1H), 8.03 (d, J=9.22 Hz, 1H), 7.37(d, J=9.16 Hz, 1H), 4.39-4.54 (m, 1H), 3.92-4.04 (m, 2H), 2.13 (d,J=12.49 Hz, 1H), 1.06-1.75 (m, 7H), 0.96 (br. S., 6H), 0.54-0.75 (m,1H).

Step 4: (6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methanol

To a mixture of methyl 6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoate (103mg, 0.271 mmol) in tetrahydrofuran (4.2 mL, 52 mmol) was added 1.00 M oflithium tetrahydroaluminate in tetrahydrofuran (0.6769 mL, 0.6769 mmol).Gas evolution observed. The reaction was then stirred at rt for 30 min,LCMS showed complete conversion. EtOAc was added and Rochele's salt wasadded and stirred for 30 min. The organic layer was washed with brine,dried and evaporated, and dried under high vacuum to give desiredproduct,(6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methanol(84 mg, 88%). LCMS: RT=2.17 min; m/z=335.10, M−H2O; ¹H NMR (400 MHz,CHLOROFORM-d) δ 8.20 (d, J=7.78 Hz, 1H), 7.91 (d, J=9.10 Hz, 1H), 7.78(s, 1H), 7.54 (d, J=8.97 Hz, 1H), 7.31 (d, J=9.16 Hz, 1H), 4.85 (s, 2H),4.30-4.49 (m, 1H), 2.11 (d, J=12.30 Hz, 2H), 1.47-1.78 (m, 4H),1.06-1.24 (m, 2H), 0.98 (s, 6H), 0.77-0.92 (m, 1H), 0.54-0.74 (m, 1H).

Step 5: 9-((6-(((trans,trans)-3,5-dimethylcyclohexloyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

To a solution of [6-((trans,trans)-3,5-dimethyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-methanol(84 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.12456 mL, 0.71512mmol) in methylene chloride (1.1 mL, 17 mmol) was added methanesulfonylchloride (0.036900 mL, 0.47674 mmol) drop wise. A white precipitateformed. The solution was stirred at rt for 1 h. LCMS showed no startingmaterial left, and complete conversion to RT=2.52 min. The mixture wasdiluted with DCM and washed with sodium bicarbonate aq solution andwater, dried over MgSO4, filtered, concentrated. The crude was thendissolved in N,N-dimethylformamide (2.8 mL, 36 mmol),9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid methyl ester; HCl salt(104.74 mg, 0.47674 mmol) was added, followed by cesium carbonate(233.00 mg, 0.71512 mmol). The reaction was then heated at 80° C. for 1h. LCMS showed no starting material left, and the completion of thereaction (RT=1.73 min.; m/z=518.3, MH+). Cooled down, the reactionmixture was diluted with EtOAc, washed with water (2×). The organicphase was then separated, dried and concentrated. The crude was purifiedby HPLC, removed the solvent, the ester was then dissolved intetrahydrofuran (1.1 mL, 14 mmol), treated with 1.0 M of lithiumhydroxide in water (1.6 mL, 1.6 mmol) at rt overnight. Acidified withconc.HCl, the organic layer was dried and concentrated. The crude wasthen purified by HLPC to give the titled compound as a white powder (32mg, 27%). LCMS: RT=1.65 min.; m/z=504.3, MH+; ¹H NMR (400 MHz,METHANOL-d4) δ 8.28 (d, J=8.91 Hz, 1H), 8.09-8.21 (m, 2H), 7.75 (d,J=10.98 Hz, 1H), 7.62 (d, J=9.29 Hz, 1H), 4.65-4.81 (m, 2H), 4.45-4.65(m, 1H), 3.67 (d, J=16.38 Hz, 2H), 3.46 (s, 2H), 2.48-2.72 (m, 2H),2.01-2.38 (m, 8H), 1.92 (d, J=10.29 Hz, 2H), 1.48-1.82 (m, 4H),1.04-1.21 (m, 2H), 0.99 (s, 6H), 0.56-0.77 (m, 1H).

Example 1048-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

Step 1: Methyl 6-((cis-4-methylcyclohexyl)oxy)-2-naphthoate

To a suspension of methyl 6-hydroxy-2-naphthoate (TCI, 809 mg, 4.00mmol), trans-4-methyl-cyclohexanol (913 mg, 8.00 mmol) andtriphenylphosphine (2.10 g, 8.00 mmol) in toluene (16 mL) at roomtemperature was added diisopropyl azodicarboxylate (1.68 mL, 8.00 mmol).During the addition, the suspension turned to a clear solution. Aftermin, LCMS shows the reaction was completed. The reaction mixture wasconcentrated and purified by flash chromatography on silica gel columnto provide the desired product as a white solid (995 mg, yield 83%). ¹HNMR (300 MHz, METHANOL-d₄) δ 8.51 (s, 1H), 7.97 (dd, J=1.51, 8.69 Hz,1H), 7.91 (d, J=8.69 Hz, 1H), 7.80 (d, J=8.69 Hz, 1H), 7.30 (d, J=2.27Hz, 1H), 7.24 (dd, J=2.46, 8.88 Hz, 1H), 4.78 (t, J=3.21 Hz, 1H), 3.96(s, 3H), 2.09 (dd, J=3.59, 13.03 Hz, 2H), 1.63-1.80 (m, 2H), 1.34-1.61(m, 5H), 0.98 (d, J=5.67 Hz, 3H); LCMS m/z 299.2 [M+H]⁺

Step 2: Methyl 5-iodo-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoate

To a mixture of methyl 6-((cis-4-methylcyclohexyl)oxy)-2-naphthoate (285mg, 0.955 mmol) and zirconium (IV) chloride (23 mg, 0.1 mmol) inmethylene chloride (5 mL) was added N-iodosuccinimide (258 mg, 1.15mmol). The reaction mixture was stirred at rt for 3 h. It was thenquenched with satd. NaS₂O₃ and extracted with EtOAc. The organic phasewas washed with satd. NaHCO₃, dried, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel column toprovide desired product as an off-white solid (341 mg, yield 84%). LCMSm/z 425.1 [M+H]⁺

Step 3: 6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoicacid

To a mixture of methyl5-iodo-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoate (212 mg, 0.500 mmol)and copper(I) iodide (171 mg, 0.899 mmol), flushed with N₂, was addedDMF (2 mL), followed by hexamethylphosphoramide (439 L, 2.50 mmol). Tothis was added methyl fluorosulphonyldifluoroacetate (328 uL, 2.50mmol), and the suspension was heated at 85° C. under N₂ atmosphere for1.5 h. The reaction mixture was diluted with EtOAc, filtered off thesolid. The organic phase was washed with brine (×3), dried over MgSO₄,concentrated to provide the crude methyl ester as an oil. LCMS m/z 367.1[M+H]⁺

The above ester was dissolved in MeOH (2 mL) and THF (2 mL), and added 3M of NaOH (0.5 mL, 1.50 mmol). The mixture was heated with microwaveirritation at 100° C. for 10 min, acidified with 1N HCl, and dilutedwith EtOAc. The organic phase was washed with brine, dried, filtered andconcentrated to get a solid, which was triturated with MeCN to get thedesired acid as an off-white solid (172 mg, 98%). ¹H NMR (300 MHz,METHANOL-d₄) δ 8.60 (d, J=1.51 Hz, 1H), 8.17-8.29 (m, 2H), 8.06-8.14 (m,1H), 7.57 (d, J=9.44 Hz, 1H), 4.97 (br. S., 1H), 1.95-2.14 (m, 2H),1.64-1.81 (m, 2H), 1.38-1.61 (m, 5H), 0.98 (d, J=5.29 Hz, 3H); LCMS m/z353.1 [M+H]⁺

Step 4:8-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

To a mixture of6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoic acid (18mg, 0.051 mmol) and methyl 8-azabicyclo[3.2.1]octane-3-carboxylate; HClsalt (13 mg, 0.063 mmol) in DMF (0.5 mL) was added HATU (23 mg, 0.060mmol), followed by N,N-diisopropylethylamine (45 uL). The mixture wasstirred at room temperature for 10 min. To the above mixture was addedAcOH (5.8 uL, 0.10 mmol), and stirred at rt for 10 min to quench thereaction. 3 M NaOH (0.2 mL, 0.6 mmol) was then added and heated withmicrowave irritation at 100° C. for 5 min. It was acidified with 1N HCl,and purified by HPLC (TFA method) to get the desired acid as a whitesolid (18 mg, yield 72%). ¹H NMR (400 MHz, METHANOL-d₄) δ 8.26 (d,J=9.04 Hz, 1H), 8.18 (d, J=9.29 Hz, 1H), 8.06 (d, J=1.51 Hz, 1H), 7.67(dd, J=1.76, 9.04 Hz, 1H), 7.58 (d, J=9.29 Hz, 1H), 4.96 (br. S., 1H),4.87 (br. S., 1H), 4.24 (br. S., 1H), 2.93-3.09 (m, 1H), 1.80-2.26 (m,10H), 1.65-1.77 (m, 2H), 1.41-1.61 (m, 5H), 0.98 (d, J=5.52 Hz, 3H);LCMS m/z 490.2 [M+H]+

Example 1059-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1:6-bromo-1-iodo-2-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene

Into a solution of2-bromo-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene (3.00 g,8.04 mmol, 1.0 eq) and NIS (1.99 g, 8.85 mmol, 1.1 eq) in CH₃CN (50 mL)was added TFA (90 mg, 0.80 mmol, 0.1 eq). The mixture was stirred at rtovernight. The solvent was removed by reduced pressure and the residuedissolved in EtOAc (100 mL). The solvent was washed with water (100 mL),dried over Na₂SO₄ and concentrated. The residue was purified by columnchromatography on silica gel (Petroleum ether/EtOAc=9/1) to give thetitled compound as a yellow solid (3.6 g, yield: 90%). ¹H NMR (400 MHz,CDCl₃) δ 8.03 (d, J=9.2 Hz, 1H), 7.88 (s, 1H), 7.68 (d, J=8.8 Hz, 1H),7.56 (dd, J=2.0 Hz, 9.2 Hz, 1H), 7.13 (d, J=9.2 Hz, 1H), 4.84 (s, 1H),2.21-2.00 (m, 5H), 1.80-1.77 (m, 2H), 1.62-1.55 (m, 2H).

Step 2:6-bromo-1-(trifluoromethyl)-2-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene

To a mixture of6-bromo-1-iodo-2-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene(3.00 g, 6.04 mmol), CuI (2.87 g, 15.10 mmol, 2.5 eq) and DIPEA (7.79 g,60.40 mmol, 10.0 eq) in DMF (50 mL) was added FSO₂CF₂CO₂CH₃ (11.59 g,60.40 mmol, 10.0 eq). The mixture stirred at 85° C. for 16 h and cooleddown. The mixture was diluted with water (200 mL) and extracted withEtOAc (100 mL×2). The combined organic layers were washed with water(200 mL) and brine (200 mL). The solvent was removed and the residue waspurified by column chromatography on silica gel (Petroleumether/EtOAc=9/1) to give the titled compound as a yellow solid (2.4 g,yield 91%).

Step 3: methyl5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate

Into an autoclave was added a solution of6-bromo-1-(trifluoromethyl)-2-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene(1.32 g, 3.0 mmol) in MeOH (50 mL), followed by PdCl₂(dppf) (245 mg, 0.3mmol, 0.1 eq) and TEA (1.26 mL, 9.0 mmol, 3.0 eq). The mixture wasstirred at 100° C. for 4 h under CO (15 atm). The mixture was cooleddown and concentrated. The crude product was purified by columnchromatography on silica gel (Petroleum ether/EtOAc=4/1) to give thetitled compound as a yellow solid (750 mg, yield 62%). ¹H NMR (400 MHz,CDCl₃) δ 8.53 (d, J=1.6 Hz, 1H), 8.26 (d, J=9.6 Hz, 1H), 8.10 (dd, J=2.0Hz, J=9.2 Hz, 1H), 8.05 (d, J=9.6 Hz, 1H), 7.32 (d, J=9.2 Hz, 1H), 4.88(s, 1H), 3.98 (s, 3H), 2.24-2.20 (m, 2H), 2.14-2.10 (m, 1H), 1.90-1.77(m, 4H), 1.68-1.56 (m, 2H); ESI-MS (M+H)⁺: 421.1.

Step 4:5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoicacid

To a mixture of methyl5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate(750 mg, 1.78 mmol) in MeOH (10 mL) was added NaOH (214 mg, 5.36 mmol,3.0 eq). The mixture was stirred at 70° C. for 2 h. Then the mixture wascooled to rt and concentrated. The residue was suspended in 3 mL ofwater and acidified to pH=6 with 1N HCl. The white solid was collectedby filtration and dried to give the titled compound (660 mg, yield 90%).¹H NMR (400 MHz, CD₃OD) δ 8.57 (d, J=1.6 Hz, 1H), 8.20-8.18 (m, 2H),8.10 (dd, J=1.6 Hz, J=9.2 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 5.02 (s, 1H),2.30-2.21 (m, 1H), 2.19-2.15 (m, 2H), 1.81-1.70 (m, 6H); ESI-MS (M+H)⁺:407.1.

Step 5:9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

To a solution of5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoicacid (120 mg, 0.30 mmol) in 3 mL of DMF were added methyl9-azabicyclo[3.3.1]nonane-3-carboxylate, HCl salt (60 mg, 0.33 mmol, 1.1eq), HOBT (60 mg, 0.45 mmol, 1.5 eq), TEA (91 mg, 0.9 mmol, 3.0 eq) andEDCI (85 mg, 0.45 mmol, 1.5 eq). The reaction mixture was stirred atroom temperature for 2 h. The solution was diluted with water (10 mL)and extracted with ethyl acetate (10 mL×3). The combined organic layerswere dried over Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography on silica gel (DCM/MeOH=50/1) to give the desiredester as a colorless oil (80 mg, yield 63%). ¹H NMR (400 MHz, CDCl₃) δ8.24 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H),7.55 (dd, J=2.0 Hz, 9.2 Hz, 1H), 7.31 (d, J=9.2 Hz, 1H), 4.98 (s, 1H),4.88-4.86 (m, 1H), 4.01-3.99 (m, 1H), 3.70 (s, 3H), 3.39-3.30 (m, 1H),2.22-2.18 (m, 2H), 2.13-1.95 (m, 6H), 1.91-1.82 (m, 8H), 1.75-1.59 (m,3H); ESI-MS (M+H)⁺: 572.2.

To a solution of the above ester (80 mg, 0.14 mmol) in MeOH/H₂O (5 mL,1:1) was added LiOH (10 mg, 0.42 mmol, 3.0 eq). The mixture was stirredat rt for 16 h. The solvent was removed by reduced pressure and theresidue was suspended in water (1 mL). The mixture was acidified with 1NHCl to pH=6. The solid was collected by filtration and purified by HPLC(MeCN/H₂O-0.05% TFA) to give the title compound as a white solid (26 mg,yield 33%). ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d, J=8.8 Hz, 1H), 8.17 (d,J=9.6 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.62-7.56 (m, 2H), 5.02 (s, 1H),3.98-3.96 (m, 1H), 3.40-3.32 (m, 1H), 2.28-2.21 (m, 1H), 2.19-2.07 (m,6H), 1.99-1.71 (m, 13H); ESI-MS (M+H)⁺: 558.2.

Example 1069-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

Step 1: methyl 2-(6-hydroxynaphthalen-2-yl)acetate

To a solution of 2-(6-hydroxynaphthalen-2-yl)acetic acid (830 mg, 4.1mmol) in 20 mL of MeOH was added 4 drops of cone. H₂SO₄. The reactionmixture was heated at reflux for 16 h and concentrated. The residue waspurified by column chromatography on silica gel (petroleumether/EtOAc=4/1) to give the title compound as a white solid (710 mg,yield 80%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 7.70 (d, J=8.8 Hz,1H), 7.64-7.62 (m, 2H), 7.28 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.09-7.05 (m,2H), 3.77 (s, 2H), 3.62 (s, 3H); ESI-MS (M+H)⁺: 216.9.

Step 2: methyl2-(6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetate

A mixture of methyl 2-(6-hydroxynaphthalen-2-yl)acetate (710 mg, 3.28mmol), trans-4-(trifluoromethyl)cyclohexyl methanesulfonate (1.2 g, 4.93mmol, 1.5 eq) and Cs₂CO₃ (1.6 g, 4.93 mmol, 1.5 eq) in 10 mL of t-BuOHwas heated at reflux for 16 h and cooled down. The mixture was pouredinto 50 mL of water and extracted with EtOAc (30 mL×3). The combinedorganics were dried and concentrated to give a dark brown solid (560 mg,yield 50%), ESI-MS (M+H)⁺: 353.1. The crude was then refluxed inmethanol with concentrated H2SO4 to convert the acid to correspondingmethyl ester. Worked up and purified on silica gel column to give thetitle compound as a white solid (535 mg, yield: 91%.) 1H NMR (400 MHz,CDCl₃) δ 7.71 (d, J=8.8 Hz, 1H), 7.68-7.65 (m, 2H), 7.36 (dd, J=1.6 Hz,8.4 Hz, 1H), 7.18-7.14 (m, 2H), 4.73-4.71 (m, 1H), 3.75 (s, 2H), 3.70(s, 3H), 2.26-2.22 (m, 2H), 2.13-2.09 (m, 1H), 1.84-1.74 (m, 4H),1.62-1.58 (m, 2H); ESI-MS (M+H)⁺: 367.1.

Step 3: methyl2-(5-iodo-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)acetate

To a solution of methyl2-(6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetate(535 mg, 1.46 mmol) in MeCN (5 mL) was added NIS (361 mg, 1.60 mmol, 1.1eq), followed by TFA (50 mg, 0.44 mmol, 0.3 eq). The mixture was stirredat rt for 16 h. The reaction mixture was diluted with water (50 mL) andextracted with EtOAc (50 mL×3). The combined organic layers were driedand concentrated. The crude product was purified by columnchromatography on silica gel (petroleum ether/EtOAc=20/1) to give thetitle compound as a white solid (500 g, yield: 70%). ¹H NMR (400 MHz,CDCl₃) δ 8.10 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.63 (s, 1H),7.45 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 4.85 (s, 1H),3.98 (s, 2H), 3.78 (s, 3H), 2.22-2.05 (m, 5H), 1.79-1.76 (m, 2H),1.61-1.55 (m, 2H).

Step 4:2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)aceticacid

The title compound was prepared according to the procedure for6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoic acidfrom methyl2-(5-iodo-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)acetate.¹H NMR (400 MHz, CD₃OD) δ 8.12 (d, J=8.8 Hz, 1H), 8.03 (d, J=9.2 Hz,1H), 7.77 (s, 1H), 7.53-7.43 (m, 2H), 4.92 (s, 1H), 3.76 (s, 2H),2.26-2.24 (m, 1H), 2.18-1.24 (m, 2H), 1.88-1.73 (m, 6H); ESI-MS (M+H)⁺:421.1.

Step 5: methyl9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate

To a solution of2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)aceticacid (200 mg, 0.476 mmol, 1.0 eq) and methyl9-azabicyclo[3.3.1]nonane-3-carboxylate, HCl salt (96 mg, 0.524 mmol,1.1 eq) in CH₂Cl₂ (10 mL) was added HATU (362 mg, 0.952 mmol, 2.0 eq),followed by TEA (96 mg, 0.952 mmol, 2.0 eq). The mixture was stirred atrt for 5 h and diluted with 20 mL of water. The mixture was extractedwith DCM (20 mL×3) and the combined organics were dried andconcentrated. The residue was purified by column chromatography onsilica gel (petroleum ether/EtOAc=4:1) to give the title compound as acolorless oil (220 mg, yield: 80%). ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d,J=8.4 Hz, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.61 (s, 1H), 7.38 (dd, J=1.6 Hz,8.8 Hz, 1H), 7.19-7.17 (m, 1H), 4.87 (s, 1H), 4.75-4.73 (m, 1H),4.08-4.06 (m, 1H), 3.76 (s, 2H), 3.57 (s, 3H), 3.19-3.15 (m, 1H),2.16-2.00 (m, 3H), 1.90-1.50 (m, 16H); ESI-MS (M+H)⁺: 586.2.

Step 6:9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the procedure for Example104 as a white solid (15 mg, yield: 23%). ¹H NMR (400 MHz, CD₃OD) δ:8.14 (d, J=8.4 Hz, 1H), 8.03 (d, J=9.2 Hz, 1H), 7.78 (s, 1H), 7.53-7.48(m, 2H), 4.98 (s, 1H), 4.85-4.82 (m, 1H), 4.35-4.32 (m, 1H), 3.95-3.92(m, 2H), 3.30-3.25 (m, 1H), 2.29-2.16 (m, 3H), 2.04-1.54 (m, 16H);ESI-MS (M+H)⁺: 572.3.

Example 1079-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1: methyl9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate

A mixture of methyl9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate(200 mg, 0.342 mmol, 1.0 eq) and BH₃/THF (3.4 mL, 1M, 3.42 mmol, 10.0eq) in THF (5 mL) was stirred at 60° C. for 6 h and diluted with 30 mLof water. The mixture was extracted with DCM (30 mL×3) and the combinedorganics were dried and concentrated. The residue was purified by columnchromatography on silica gel (petroleum ether/EtOAc=4:1) to give thetitle compound as a white solid (60 mg, yield: 31%). ESI-MS (M+H)⁺:572.1.

Step 2:9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the procedure for Example104 as a white solid (40 mg, yield: 69%). ¹H NMR (400 MHz, CD₃OD) δ 8.19(d, J=8.8 Hz, 1H), 8.08 (d, J=9.2 Hz, 1H), 7.85 (s, 1H), 7.57 (d, J=8.8Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 4.98 (s, 1H), 3.81-3.78 (m, 2H),3.70-3.60 (m, 2H), 3.46-3.36 (m, 1H), 3.28-3.19 (m, 2H), 2.38-2.24 (m,6H), 2.22-2.01 (m, 5H), 1.90-1.70 (m, 8H). ESI-MS (M+H)⁺: 558.1.

Example 1089-((6-((cis-4-methylcyclohexyl)amino)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1: Methyl 6-((cis-4-(methyl)cyclohexyl)amino)-2-naphthoate

To a solution of methyl 6-amino-2-naphthoate (1.2 g, 6.0 mmol, 1.0 eq)and 4-methylcyclohexanone (900 mg, 8.0 mmol, 1.3 eq) in DCE (20 mL) wereadded NaBH(Oac)₃ (2.6 g, 12.0 mmol, 2.0 eq) and HOAc (720 mg, 12.0 mol,2.0 eq). The mixture was stirred at 80° C. for 16 h and cooled down. Themixture was partitioned between DCM (30 mL) and sat. aq. NaHCO₃ (30 mL).The organic layer was dried over Na₂SO₄ and concentrated to yield acrude product, which was washed with MeOH (5 mL×3) to give the titlecompound as a yellow solid (712 mg, yield: 40%). ¹H NMR (400 MHz, CDCl₃)δ 8.39 (s, 1H), 7.91 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H),7.56 (d, J=8.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.79 (s, 1H), 3.94 (s,3H), 3.72-3.69 (m, 1H), 1.87-1.81 (m, 2H), 1.77-1.67 (m, 2H), 1.62-1.59(m, 3H), 1.31-1.21 (m, 2H), 0.95 (d, J=6.4 Hz, 3H); ESI-MS (M+H)⁺:298.2.

Step 2: (6-((cis-4-(methyl)cyclohexyl)amino)naphthalen-2-yl)methanol

To a solution of methyl 6-((cis-4-(methyl)cyclohexyl)amino)-2-naphthoate(179 mg, 0.6 mmol, 1.0 eq) in dry THF (2 mL) was added LiAlH₄ (31 mg,0.8 mmol, 1.5 eq) at 0° C. The mixture was stirred at 0° C. for 2 h andquenched with Na₂SO₄.10H₂O. The mixture was diluted with water (15 mL)and extracted with EtOAc (15 mL×2). The combined organic layers weredried and concentrated to give the title compound as a yellow oil, whichwas used for the next step without further purification (130 mg, yield:80%). ESI-MS (M+H)⁺: 270.2.

Step 3: 6-((cis-4-(methyl)cyclohexyl)amino)-2-naphthaldehyde

A mixture of(6-((cis-4-(methyl)cyclohexyl)amino)naphthalen-2-yl)methanol (134 mg,0.5 mmol, 1.0 eq) and MnO₂ (440 mg, 5.0 mmol, 10.0 eq) in DCM (5 mL) wasstirred at rt for 16 h. The mixture was filtered and the filtrate wasconcentrated to give the title compound as a yellow oil, which was usedfor the next step without further purification (81 mg, yield: 60%).ESI-MS (M+H)⁺: 268.2.

Step 4:6-((cis-4-methylcyclohexyl)amino)-5-(trifluoromethyl)-2-naphthaldehyde

A mixture of 6-((cis-4-(methyl)cyclohexyl)amino)-2-naphthaldehyde (400mg, 1.5 mmol, 1.0 eq) and1-trifluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole (referencesee M. S. Wiehn et al. J. Fluorine Chem. 131 (2010) P-951, which isincorporated by reference in its entirety) (741 mg, 2.25 mmol, 1.5 eq)in CAN (4 mL) was heated at 80° C. for 16 h in a sealed tube. Themixture was cooled to rt, and partitioned between DCM (30 mL) and H₂O(30 mL). The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by column chromatography on silica gel (petroleumether/EtOAc=6/1) to give the title compound as a yellow solid (200 mg,yield: 60%). ¹H NMR (400 MHz, CDCl₃) δ 10.04 (s, 1H), 8.14 (d, J=1.6 Hz,1H), 8.03 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.92-7.87 (m, 2H), 7.14 (d, J=9.6Hz, 1H), 3.86-3.84 (m, 1H), 1.87-1.83 (m, 2H), 1.76-1.68 (m, 2H),1.65-1.55 (m, 3H), 1.27-1.21 (m, 2H), 0.97 (d, J=6.4 Hz, 3H); ESI-MS(M+H)⁺: 336.2.

Step 5:9-((6-((cis-4-methylcyclohexyl)amino)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

To a mixture of 9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid methylester HCl salt (26 mg, 0.12 mmol) in THF (0.7 mL) was addedtriethylamine (17 μL, 0.12 mmol), and stirred at rt for 15 min. To thismixture was added6-((cis-4-methylcyclohexyl)amino)-5-(trifluoromethyl)-2-naphthaldehyde(34 mg, 0.10 mmol), followed by sodium triacetoxyborohydride (28 mg,0.13 mmol) and acetic acid (6.8 μL, 0.12 mmol). The reaction mixture washeated with microwave irritation at 100° C. for 20 min. To the abovemixture was added 3 M of NaOH in water (0.5 mL, 2 mmol) and MeOH (0.8mL). The reaction mixture was heated with microwave irritation at 100°C. for 10 min, It was neutralized with 1N HCl, filtered and purified byHPLC (TFA method) to collect the desired acid as a white powder afterlyophilization (35 mg, yield 58%). ¹H NMR (300 MHz, METHANOL-d₄) δ7.83-8.11 (m, 3H), 7.60 (d, J=9.06 Hz, 1H), 7.30 (d, J=9.44 Hz, 1H),4.50-4.73 (m, 2H), 3.92 (br. S., 1H), 3.62 (br. S., 2H), 3.34-3.47 (m,1H), 2.47-2.65 (m, 2H), 1.99-2.38 (m, 6H), 1.45-1.96 (m, 9H), 1.12-1.36(m, 2H), 0.97 (d, J=6.42 Hz, 3H); LCMS m/z 489.1 [M+H]⁺

Example 1092-(9-Azabicyclo[3.3.1]nonan-9-yl)-2-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)aceticacid

Step 1:(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)boronicacid

To a solution of6-bromo-2-((cis-4-methylcyclohexyl)oxy)-1-(trifluoromethyl) naphthalene,prepared according to the procedure for6-bromo-1-(trifluoromethyl)-2-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalenefrom trans-4-methylcyclohexanol (774 mg, 2.00 mmol) in THF (4 mL) at−78° C. was added 2.5 M of n-butyllithium in hexane (0.96 mL, 2.4 mmol)dropwise under N₂. The reaction mixture was stirred at −78° C. for 30min. Triisopropyl borate (0.69 mL, 3.0 mmol) was added, and stirred at−78° C. for 1 h. The reaction was quenched with 1N HCl, and extractedwith EtOAc. The organic phase was washed with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by flashchromatography on silica gel column, eluted with EtOAc/MeOH/AcOH(100:10:1) to get the desired boronic acid as a white solid (234 mg,yield 33%). ¹H NMR (300 MHz, METHANOL-d₄) δ 8.00-8.19 (m, 3H), 7.76 (dd,J=1.13, 8.69 Hz, 1H), 7.45 (d, J=9.06 Hz, 1H), 4.89 (br, s, 1H),1.91-2.15 (m, 2H), 1.59-1.79 (m, 2H), 1.38-1.57 (m, 5H), 0.96 (d, J=5.29Hz, 3H); LCMS m/z 353.1 [M+H]⁺

Step 2:2-(9-Azabicyclo[3.3.1]nonan-9-yl)-2-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)aceticacid

To a mixture of glyoxalic acid hydrate (21 mg, 0.23 mmol) and(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)boronicacid (67 mg, 0.19 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (2 mL) wasadded 9-azabicyclo[3.3.1]nonane HCl salt (46 mg, 0.28 mmol). To theabove suspension was added N,N-diisopropylethylamine (50 μL, 0.28 mmol),and stirred at rt for 2 days. The mixture was purified by HPLC (TFAmethod) to collect the desired product as a white powder afterlyophilization (3 mg, yield 3%). ¹H NMR (300 MHz, METHANOL-d₄) δ8.22-8.28 (m, 2H), 8.10 (d, J=9.06 Hz, 1H), 7.87 (d, J=9.44 Hz, 1H),7.57 (d, J=9.06 Hz, 1H), 5.50 (s, 1H), 4.93 (br. S., 1H), 3.38-4.03 (m,2H), 1.23-2.35 (m, 21H), 0.95 (d, J=5.29 Hz, 3H); LCMS m/z 490.1.1[M+H]⁺

Example 1109-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1: 5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthaldehyde

The solution of 6-((cis-4-ethylcyclohexyl)oxy)-2-naphthaldehyde (1.41 g,5.00 mmol), N-chlorosuccinimide (801 mg, 6.00 mmol) in acetonitrile (10mL) was heated with microwave irritation at 100° C. for 20 min. Themixture was partitioned between EtOAc and brine. The organic phase waswashed with brine, dried over MgSO₄, filtered and concentrated to getthe desired aldehyde as a pale yellow solid (1.84 g, yield 100%). LCMSm/z 317.0 [M+H]⁺

Step 2:9-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

To a mixture of 9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid methylester HCl salt (46 mg, 0.21 mmol) and5-chloro-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthaldehyde (56 mg, 0.15mmol) in THF (1 mL) was added sodium triacetoxyborohydride (46 mg, 0.22mmol). The reaction solution was heated with microwave irritation at100° C. for 20 min.

To the above mixture was added 3 M of NaOH in water (0.8 mL, 2 mmol) andMeOH (0.8 mL), and heated with microwave irritation at 100° C. for 10min. It was neutralized with 1N HCl. Filtered and purified by HPLC (TFAmethod) to collect the TFA salt of the desired product as a white powderafter lyophilization (47 mg, yield 53%). ¹H NMR (300 MHz, METHANOL-d₄) δ8.29 (d, J=8.69 Hz, 1H), 8.09 (s, 1H), 7.90 (d, J=9.44 Hz, 1H), 7.74(dd, J=1.89, 8.69 Hz, 1H), 7.52 (d, J=9.06 Hz, 1H), 4.88 (br. S., 1H),4.61-4.75 (m, 2H), 3.64 (br. S., 2H), 3.41 (t, J=9.25 Hz, 1H), 2.56 (br.S., 2H), 1.42-2.39 (m, 16H), 1.17-1.40 (m, 3H), 0.93 (t, J=6.99 Hz, 3H);LCMS m/z 470.0 [M+H]⁺

Example 1119-((5-Chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1: Methyl9-((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate

To a mixture of6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthaldehyde (161 mg,0.500 mmol) and 9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid methylester HCl salt (132 mg, 0.600 mmol) in THF (2 mL) was added acetic acid(43 μL, 0.76 mmol) and sodium triacetoxyborohydride (159 mg, 0.750mmol). The reaction mixture was then heated with microwave irritation at100° C. for 20 min. It was partitioned between EtOAc and brine. Theorganic phase was washed with brine, dried, filtered and concentrated.The residue was purified by flash chromatography on silica gel column toget the desired ester as a colorless oil (215 mg, yield 88%). LCMS m/z490.1 [M+H]⁺

Step 2:9-((5-Chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The solution of methyl9-((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate(98 mg, 0.20 mmol), N-chlorosuccinimide (41 mg, 0.31 mmol) inacetonitrile (1 mL) was heated with microwave irritation at 80° C. for20 min. The mixture was purified by HPLC (TFA method) to get the esterintermediate (53 mg, yield 42%). LCMS m/z 524.0 [M+H]⁺.

The above ester was dissolved in THF (0.6 mL) and MeOH (0.6 mL), added 3M of NaOH in water (0.2 mL, 0.6 mmol), and heated at 50° C. (hot plate)for 1 h. It was neutralized with 1N HCl, and purified by HPLC (TFAmethod) to get the desired product as a white powder afterlyophilization (34 mg, yield 64%). ¹H NMR (400 MHz, METHANOL-d₄) δ 8.32(d, J=8.78 Hz, 1H), 8.11 (br. S., 1H), 7.93 (d, J=9.04 Hz, 1H), 7.75 (d,J=8.78 Hz, 1H), 7.55 (d, J=9.04 Hz, 1H), 4.95 (br. S., 1H), 4.61-4.78(m, 2H), 3.65 (d, J=15.56 Hz, 2H), 3.36-3.46 (m, 1H), 2.58 (d, J=9.29Hz, 2H), 2.02-2.38 (m, 9H), 1.64-2.01 (m, 8H); LCMS m/z 510.0 [M+H]⁺.

Example 1124-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylicacid

To a solution of(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methanaminehydrochloride salt (100 mg, 0.25 mmol) in 2 mL of DMF were added4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (60 mg, 0.28mmol, 1.1 eq), HOBT (51 mg, 0.38 mmol, 1.5 eq), TEA (76 mg, 0.75 mmol,3.0 eq) and EDCI (73 mg, 0.38 mmol, 1.5 eq). The reaction mixture wasstirred at room temperature for 16 h. The solution was diluted withwater (10 mL) and extracted with ethyl acetate (10 mL×3). The combinedorganic layers were dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography on silica gel (DCM/MeOH=50/1) to givethe corresponding methyl ester as a colorless oil (56 mg, yield: 37%).ESI-MS (M+H)⁺: 586.2.

To a solution of the above ester (56 mg, 0.096 mmol) in MeOH/H2O (5 mL,1:1) was added NaOH (12 mg, 0.287 mmol, 3.0 eq). The mixture was stirredat 65° C. overnight. The solvent was removed by reduced pressure and theresidue was suspended in water (1 mL). The mixture was acidified with 1NHCl to pH=6. The resulting mixture was purified by reversed HPLC(MeCN/H2O-0.05% TFA) to give the title compound as a white solid (30 mg,yield: 55%). ¹H NMR (400 MHz, CD3OD) δ 8.01 (d, J=8.4 Hz, 1H), 7.91 (d,J=9.6 Hz, 1H), 7.60 (s, 1H), 7.38-7.35 (m, 2H), 4.85 (s, 1H), 4.39 (m,2H), 2.20-2.05 (m, 3H), 1.75-1.56 (m, 18H); ESI-MS (M+H) +: 572.1.

Example 113N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-1-aminoindane-6-carboxylicacid

The title compound was prepared according to the method of Example 105.¹H NMR (400 MHz, CD₃OD) δ: 8.43 (d, J=1.6 Hz, 1H), 8.22 (d, J=8.4 Hz,1H), 8.17 (d, J=9.2 Hz, 1H), 8.03 (dd, J=2.4 Hz, 9.6 Hz, 1H), 7.98 (s,1H), 7.92 (d, J=7.6 Hz, 1H), 7.55 (d, J=9.6 Hz, 1H), 7.37 (d, J=8.0 Hz,1H), 5.74-5.71 (m, 1H), 5.01 (s, 1H), 3.17-3.10 (m, 1H), 3.03-2.97 (m,1H), 2.69-2.65 (m, 1H), 2.27-2.24 (m, 1H), 2.18-2.09 (m, 3H), 1.83-1.72(m, 6H); ESI-MS (M+H)+: 566.2.

Example 114N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-6-aminoindole-3-carboxylicacid

The title compound was prepared according to the method of Example 105.¹H NMR (400 MHz, CD₃OD) δ: 8.44 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.14(d, J=9.2 Hz, 1H), 8.05 (d, J=1.2 Hz, 1H), 8.02 (dd, J=2.0 Hz, 9.2 Hz,1H), 7.95 (d, J=9.2 Hz, 1H), 7.86 (s, 1H), 7.50 (d, J=9.6 Hz, 1H), 7.28(dd, J=2.0 Hz, 8.8 Hz, 1H), 4.94 (s, 1H), 2.20-2.17 (m, 1H), 2.11-2.08(m, 2H), 1.76-1.62 (m, 6H); ESI-MS (M+H)⁺: 565.1.

Example 115N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-2-azabicyclo[1.2.3]octane-7-carboxylicacid

The title compound was prepared according to the method of Example 105.¹H NMR (400 MHz, CD₃OD) δ: 8.14 (d, J=7.2 Hz, 1H), 8.08 (d, J=9.2 Hz,1H), 7.98 (d, J=1.6 Hz, 1H), 7.58 (dd, J=2.0 Hz, 9.6 Hz, 1H), 7.47 (d,J=9.6 Hz, 1H), 4.92 (s, 1H), 4.74-4.72 (m, 1H), 4.05-4.02 (m, 1H),2.73-2.64 (m, 1H), 2.21-2.06 (m, 3H), 1.97-1.60 (m, 14H); ESI-MS (M+H)⁺:544.1.

Example 116N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-decahydroisoquinoline-5-carboxylicacid

The title compound was prepared according to the method of Example 105.¹H NMR (400 MHz, CD₃OD) δ: 8.22 (d, J=8.8 Hz, 1H), 8.14 (d, J=8.8 Hz,1H), 7.94 (s, 1H), 7.58-7.54 (m, 2H), 5.01 (s, 1H), 4.53-4.42 (m, 1H),3.91-3.88 (m, 1H), 3.58-3.50 (m, 1H), 3.38-3.32 (m, 1H), 2.48-2.38 (m,1H), 2.27-2.20 (m, 1H), 2.18-2.15 (m, 2H), 2.02-1.48 (m, 13H), 1.45-1.30(m, 3H); ESI-MS (M+H)⁺: 572.2.

Example 1172-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-2-azabicyclo[1.2.3]octane-7-carboxylic acid

The title compound was prepared according to the method of Example 106.¹H NMR (400 MHz, CD₃OD) δ: 8.13 (d, J=7.2 Hz, 1H), 8.03 (d, J=9.2 Hz,1H), 7.78 (s, 1H), 7.52 (dd, J=1.6 Hz, 9.2 Hz, 1H), 7.48 (d, J=9.2 Hz,1H), 4.97 (s, 1H), 4.70-4.69 (m, 1H), 4.51-4.49 (m, 1H), 3.90 (AB, 2H),2.95-2.89 (m, 1H), 2.29-2.16 (m, 3H), 2.00-1.61 (m, 14H). ESI-MS (M+H)⁺:558.1

Example 1182-(2-(5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-2-azabicyclo[1.2.3]octane-7-carboxylic acid

The title compound was prepared according to the method of Example 106.¹H NMR (400 MHz, DMSO-d₆) δ: 12.53 (br s, 1H), 8.28 (d, J=8.8 Hz, 1H),8.16 (d, J=9.2 Hz, 2H), 7.78-7.51 (m, 3H), 5.05 (s, 1H), 4.30 (s, 2H),3.91 (s, 2H), 2.89-2.83 (m, 1H), 2.46-2.37 (m, 2H), 2.13-1.56 (m, 15H);ESI-MS (M+H)⁺: 512.3

Example 1194-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)aminomethyl)bicyclo[2.2.2]octane-1-carboxylicacid

The title compound was prepared according to the method of Example 85.¹H NMR (400 MHz, CD₃OD) δ: 8.16 (d, J=8.4 Hz, 1H), 8.03 (d, J=9.2 Hz,1H), 7.94 (d, J=1.2 Hz, 1H), 7.57 (dd, J=2.0 Hz, 9.2 Hz, 1H), 7.49 (d,J=9.2 Hz, 1H), 4.92 (s, 1H), 4.28 (s, 2H), 2.72 (s, 2H), 2.19-2.06 (m,3H), 1.74-1.65 (m, 12H), 1.45-1.41 (m, 6H). ESI-MS (M+H)⁺: 558.2

Example 1204-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-2-hydroxybicyclo[2.2.2]octane-1-carboxylicacid

The title compound was prepared according to the method of Example 85.¹H NMR (400 MHz, CD₃OD) d: 8.15 (d, J=8.0 Hz, 1H), 8.04 (d, J=9.2 Hz,1H), 7.94 (d, J=2.0 Hz, 1H), 7.56 (dd, J=1.6 Hz, 9.2 Hz, 1H), 7.48 (d,J=9.6 Hz, 1H), 4.92 (s, 1H), 4.30-4.28 (m, 2H), 4.20 (s, 1H), 2.35-2.09(m, 5H), 1.92-1.81 (m, 8H), 1.79-1.61 (m, 6H); ESI-MS (M+H)⁺: 559.9

Example 1217-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-tricyclo[3.1.1.0]heptane-5-carboxylicacid

The title compound was prepared according to the method of Example 85.¹H NMR (400 MHz, CD₃OD) δ: 8.16 (d, J=8.8 Hz, 1H), 8.04 (d, J=9.2 Hz,1H), 7.96 (s, 1H), 7.59 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.49 (d, J=9.2 Hz,1H), 4.92 (s, 1H), 4.34-4.31 (m, 2H), 3.31-3.29 (m, 1H), 2.91 (s, 0.5H),2.60 (s, 0.5H), 2.55 (s, 0.5H), 2.49 (s, 0.5H), 2.21-2.02 (m, 3H),1.78-1.45 (m, 11H). ESI-MS (M+H)⁺: 528.1

Example 1228-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalene-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 88.¹H NMR (400 MHz, CD₃OD) δ: 8.22 (d, J=8.4 Hz, 1H), 8.05 (d, J=9.2 Hz,1H), 7.94 (s, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 4.93(s, 1H), 4.46-4.45 (m, 1H), 4.33-4.28 (m, 1H), 3.38-3.36 (m, 1H),2.90-2.83 (m, 1H), 2.48-2.40 (m, 1H), 2.22-2.02 (m, 7H), 1.92-1.81 (m,3H), 1.73-1.61 (m, 9H). ESI-MS (M+H)⁺: 543.9

Example 1233-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)-7,7-dimethylbicyclo[2.2.1]heptane-4-carboxylicacid

The title compound was prepared according to the method of Example 85.¹H NMR (400 MHz, CD₃OD) δ: 8.30 (d, J=8.4 Hz, 1H), 8.04 (d, J=8.8 Hz,1H), 7.93 (s, 1H), 7.59 (d, J=9.2 Hz, 1H), 7.47 (d, J=9.2 Hz, 1H), 4.91(s, 1H), 4.21-4.11 (m, 2H), 2.33-2.30 (m, 1H), 2.19-2.06 (m, 3H),1.84-1.60 (m, 8H), 1.33-1.06 (m, 5H), 0.97 (s, 6H). ESI-MS (M+H)⁺: 557.9

Example 1248-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 93.¹H NMR (300 MHz, METHANOL-d₄) δ 8.32 (d, J=8.31 Hz, 1H), 8.13 (d, J=9.06Hz, 1H), 8.03 (d, J=1.89 Hz, 1H), 7.72 (dd, J=1.89, 9.06 Hz, 1H), 7.60(d, J=9.44 Hz, 1H), 4.96 (br. s., 1H), 4.57 (d, J=6.42 Hz, 1H), 4.41 (q,J=6.67 Hz, 1H), 3.49 (d, J=6.04 Hz, 1H), 2.88-3.06 (m, 1H), 2.48-2.61(m, 1H), 1.90-2.40 (m, 9H), 1.84 (d, J=6.42 Hz, 3H), 1.72 (t, J=12.84Hz, 2H), 1.37-1.61 (m, 5H), 0.97 (d, J=5.29 Hz, 3H); LCMS m/z 490.3[M+H]+

Example 1259-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 104.¹H NMR (400 MHz, METHANOL-d₄) δ 8.26 (d, J=8.53 Hz, 1H), 8.16 (d, J=9.29Hz, 1H), 7.98 (d, J=1.51 Hz, 1H), 7.61 (dd, J=1.76, 9.04 Hz, 1H), 7.57(d, J=9.29 Hz, 1H), 4.90-4.98 (m, 2H), 4.01 (br. s., 1H), 3.31-3.45 (m,1H), 1.85-2.25 (m, 10H), 1.63-1.82 (m, 4H), 1.40-1.60 (m, 5H), 0.98 (d,J=5.52 Hz, 3H); LCMS m/z 504.3 [M+H]+

Example 1269-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-aza-7-oxa-bicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 97.¹H NMR (400 MHz, METHANOL-d₄) δ 8.28 (d, J=8.28 Hz, 1H), 8.08-8.19 (m,2H), 7.72 (dd, J=1.76, 9.04 Hz, 1H), 7.58 (d, J=9.29 Hz, 1H), 4.94 (br.s., 1H), 4.80 (br. s., 2H), 3.75-4.08 (m, 1H), 3.70-3.85 (m, 1H),3.50-3.59 (m, 2H), 3.18-3.26 (m, 2H), 2.33-2.38 (m, 2H), 1.96-2.13 (m,2H), 1.70 (t, J=13.18 Hz, 2H), 1.37-1.60 (m, 5H), 0.96 (d, J=5.77 Hz,3H); LCMS m/z 492.2 [M+H]+

Example 1278-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 93.¹H NMR (400 MHz, METHANOL-d₄) δ 8.32 (d, J=8.78 Hz, 1H), 8.12 (d, J=9.29Hz, 1H), 8.01 (s, 1H), 7.67 (d, J=9.29 Hz, 1H), 7.59 (d, J=9.29 Hz, 1H),4.95 (br. s., 1H), 4.58 (d, J=6.27 Hz, 1H), 4.09 (dd, J=3.01, 11.55 Hz,1H), 3.41 (d, J=2.01 Hz, 1H), 2.84-3.03 (m, 1H), 2.35-2.65 (m, 2H),2.01-2.32 (m, 8H), 1.87-1.99 (m, 2H), 1.70 (t, J=13.05 Hz, 2H),1.35-1.59 (m, 5H), 0.96 (d, J=5.77 Hz, 3H), 0.78 (t, J=7.28 Hz, 3H);LCMS m/z 504.3 [M+H]+

Example 1289-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 93.¹H NMR (400 MHz, METHANOL-d₄) δ 8.33 (br. s., 1H), 8.06-8.22 (m, 2H),7.76 (d, J=7.78 Hz, 1H), 7.61 (d, J=9.29 Hz, 1H), 4.97 (br. s., 1H),4.72-4.95 (m, 1H), 4.18-4.32 (m, 1H), 3.30-3.49 (m, 1H), 3.09-3.23 (m,1H), 1.37-2.63 (m, 21H), 0.98 (d, J=5.77 Hz, 3H), 0.77 (t, J=7.28 Hz,3H); LCMS m/z 518.3 [M+H]+

Example 1299-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-7-hydroxy-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 97.¹H NMR (400 MHz, METHANOL-d₄) δ 8.28 (d, J=8.53 Hz, 1H), 8.07-8.18 (m,2H), 7.72 (d, J=7.78 Hz, 1H), 7.59 (d, J=9.29 Hz, 1H), 4.95 (br. s.,1H), 4.55-4.72 (m, 2H), 4.48-4.53 (m, 1H), 4.02-4.30 (m, 1H), 3.62-3.81(m, 2H), 2.22-2.88 (m, 4H), 1.80-2.28 (m, 7H), 1.70 (t, J=13.05 Hz, 2H),1.36-1.59 (m, 5H), 0.96 (d, J=5.77 Hz, 3H); LCMS m/z 506.3 [M+H]+

Example 1308-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 1

The title compound was prepared according to the method of Example 94.¹H NMR (400 MHz, METHANOL-d₄) δ 8.33 (d, J=8.78 Hz, 1H), 8.14 (d, J=9.29Hz, 1H), 8.04 (d, J=1.51 Hz, 1H), 7.73 (dd, J=1.63, 9.16 Hz, 1H), 7.60(d, J=9.29 Hz, 1H), 4.96 (br. s., 1H), 4.51-4.63 (m, 1H), 4.41 (q,J=6.53 Hz, 1H), 3.46-3.55 (m, 1H), 2.89-3.04 (m, 1H), 2.48-2.66 (m, 1H),2.12-2.41 (m, 4H), 1.91-2.10 (m, 5H), 1.84 (d, J=6.78 Hz, 3H), 1.72 (t,J=13.05 Hz, 2H), 1.39-1.60 (m, 5H), 0.98 (d, J=5.77 Hz, 3H); LCMS m/z490.2 [M+H]+

Example 1318-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 2

The title compound was prepared according to the method of Example 95.¹H NMR (400 MHz, METHANOL-d₄) δ 8.31 (d, J=8.78 Hz, 1H), 8.12 (d, J=9.29Hz, 1H), 8.02 (s, 1H), 7.71 (dd, J=1.76, 9.04 Hz, 1H), 7.58 (d, J=9.29Hz, 1H), 4.94 (br. s., 1H), 4.47-4.61 (m, 1H), 4.39 (q, J=6.53 Hz, 1H),3.43-3.52 (m, 1H), 2.95 (tt, J=6.09, 11.73 Hz, 1H), 2.47-2.63 (m, 1H),2.10-2.38 (m, 4H), 1.89-2.09 (m, 5H), 1.83 (d, J=6.53 Hz, 3H), 1.70 (t,J=13.18 Hz, 2H), 1.36-1.58 (m, 5H), 0.96 (d, J=5.77 Hz, 3H); LCMS m/z490.3 [M+H]+

Example 1329-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 99.¹H NMR (400 MHz, METHANOL-d₄) δ 8.43 (d, J=8.78 Hz, 1H), 8.07 (dd,J=9.41, 15.69 Hz, 2H), 7.40-7.79 (m, 3H), 4.99-5.26 (m, 1H), 4.88 (br.s., 1H), 4.11-4.27 (m, 1H), 3.34-3.46 (m, 1H), 3.08-3.24 (m, 1H),1.82-2.63 (m, 11H), 1.78 (d, J=6.53 Hz, 3H), 1.71 (t, J=13.43 Hz, 3H),1.49-1.63 (m, 3H), 1.25-1.32 (m, 2H), 0.98 (d, J=6.02 Hz, 3H); LCMS m/z486.1 [M+H]+

Example 1338-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 99.¹H NMR (400 MHz, METHANOL-d₄) δ 8.44 (d, J=8.78 Hz, 1H), 8.05 (d, J=9.04Hz, 1H), 8.00 (s, 1H), 7.41-7.76 (m, 3H), 4.89 (br. s., 1H), 4.51-4.61(m, 1H), 4.38 (q, J=6.53 Hz, 1H), 3.44-3.53 (m, 1H), 2.95 (tt, J=6.12,11.70 Hz, 1H), 2.47-2.63 (m, 1H), 2.10-2.36 (m, 4H), 1.89-2.09 (m, 5H),1.83 (d, J=6.78 Hz, 3H), 1.65-1.76 (m, 2H), 1.49-1.63 (m, 3H), 1.25-1.42(m, 2H), 0.98 (d, J=6.27 Hz, 3H); LCMS m/z 472.1 [M+H]+

Example 1348-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 99.¹H NMR (400 MHz, METHANOL-d₄) δ 8.41 (d, J=8.78 Hz, 1H), 7.98-8.13 (m,2H), 7.42-7.77 (m, 3H), 4.87-4.92 (m, 1H), 4.34 (s, 2H), 4.02 (br. s.,2H), 2.89-3.08 (m, 1H), 2.42-2.63 (m, 2H), 1.96-2.23 (m, 8H), 1.71 (t,J=13.43 Hz, 2H), 1.49-1.63 (m, 3H), 1.23-1.42 (m, 2H), 0.98 (d, J=6.02Hz, 3H); LCMS m/z 458.1 [M+H]+

Example 1359-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

¹H NMR (400 MHz, METHANOL-d₄) δ 8.45 (d, J=6.27 Hz, 1H), 8.00-8.14 (m,2H), 7.41-7.78 (m, 3H), 4.87-4.94 (m, 1H), 4.69-4.79 (m, 1H), 4.20-4.31(m, 1H), 3.34-3.47 (m, 1H), 3.07-3.21 (m, 1H), 1.80-2.63 (m, 13H),1.48-1.78 (m, 6H), 1.24-1.43 (m, 2H), 0.98 (d, J=6.02 Hz, 3H), 0.76 (t,J=7.28 Hz, 3H); LCMS m/z 500.1 [M+H]+

Example 1368-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 1

The title compound was prepared according to the method of Example 133and purified by chiral chromatography. ¹H NMR (400 MHz, METHANOL-d₄) δ8.44 (d, J=8.78 Hz, 1H), 8.05 (d, J=9.04 Hz, 1H), 8.00 (s, 1H),7.41-7.76 (m, 3H), 4.89 (br. s., 1H), 4.51-4.61 (m, 1H), 4.38 (q, J=6.53Hz, 1H), 3.44-3.53 (m, 1H), 2.95 (tt, J=6.12, 11.70 Hz, 1H), 2.47-2.63(m, 1H), 2.10-2.36 (m, 4H), 1.89-2.09 (m, 5H), 1.83 (d, J=6.78 Hz, 3H),1.65-1.76 (m, 2H), 1.49-1.63 (m, 3H), 1.25-1.42 (m, 2H), 0.98 (d, J=6.27Hz, 3H); LCMS m/z 472.1 [M+H]+

Example 1378-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 1

The title compound was prepared according to the method of Example 133and purified by chiral chromatography. ¹H NMR (400 MHz, METHANOL-d₄) δ8.44 (d, J=8.78 Hz, 1H), 8.05 (d, J=9.04 Hz, 1H), 8.00 (s, 1H),7.41-7.76 (m, 3H), 4.89 (br. s., 1H), 4.51-4.61 (m, 1H), 4.38 (q, J=6.53Hz, 1H), 3.44-3.53 (m, 1H), 2.95 (tt, J=6.12, 11.70 Hz, 1H), 2.47-2.63(m, 1H), 2.10-2.36 (m, 4H), 1.89-2.09 (m, 5H), 1.83 (d, J=6.78 Hz, 3H),1.65-1.76 (m, 2H), 1.49-1.63 (m, 3H), 1.25-1.42 (m, 2H), 0.98 (d, J=6.27Hz, 3H); LCMS m/z 472.1 [M+H]+

Example 1389-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid, enantiomer 1

The title compound was prepared according to the method of Example 132,and purified by chiral chromatography. ¹H NMR (400 MHz, METHANOL-d₄) δ8.43 (d, J=8.78 Hz, 1H), 8.07 (dd, J=9.41, 15.69 Hz, 2H), 7.40-7.79 (m,3H), 4.99-5.26 (m, 1H), 4.88 (br. s., 1H), 4.11-4.27 (m, 1H), 3.34-3.46(m, 1H), 3.08-3.24 (m, 1H), 1.82-2.63 (m, 11H), 1.78 (d, J=6.53 Hz, 3H),1.71 (t, J=13.43 Hz, 3H), 1.49-1.63 (m, 3H), 1.25-1.32 (m, 2H), 0.98 (d,J=6.02 Hz, 3H); LCMS m/z 486.1 [M+H]+

Example 1399-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid, enantiomer 2

The title compound was prepared according to the method of Example 132,and purified by chiral chromatography. ¹H NMR (400 MHz, METHANOL-d₄) δ8.43 (d, J=8.78 Hz, 1H), 8.07 (dd, J=9.41, 15.69 Hz, 2H), 7.40-7.79 (m,3H), 4.99-5.26 (m, 1H), 4.88 (br. s., 1H), 4.11-4.27 (m, 1H), 3.34-3.46(m, 1H), 3.08-3.24 (m, 1H), 1.82-2.63 (m, 11H), 1.78 (d, J=6.53 Hz, 3H),1.71 (t, J=13.43 Hz, 3H), 1.49-1.63 (m, 3H), 1.25-1.32 (m, 2H), 0.98 (d,J=6.02 Hz, 3H); LCMS m/z 486.1 [M+H]+

Example 1408-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 1

The title compound was prepared according to the method of Example 99,and purified by chiral chromatography. ¹H NMR (400 MHz, METHANOL-d₄) δ8.45 (d, J=8.78 Hz, 1H), 8.05 (d, J=9.29 Hz, 1H), 7.99 (s, 1H),7.40-7.78 (m, 3H), 4.89 (br. s., 1H), 4.51-4.65 (m, 1H), 4.07 (dd,J=3.26, 11.55 Hz, 1H), 3.37-3.50 (m, 1H), 2.86-3.05 (m, 1H), 2.49-2.64(m, 1H), 2.35-2.48 (m, 1H), 1.86-2.33 (m, 10H), 1.65-1.80 (m, 2H),1.46-1.63 (m, 3H), 1.27-1.42 (m, 2H), 0.98 (d, J=6.27 Hz, 3H), 0.79 (t,J=7.28 Hz, 3H); LCMS m/z 486.1 [M+H]+

Example 1418-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 2

The title compound was prepared according to the method of Example 99,and purified by chiral chromatography. ¹H NMR (400 MHz, METHANOL-d₄) δ8.45 (d, J=8.78 Hz, 1H), 8.05 (d, J=9.29 Hz, 1H), 7.99 (s, 1H),7.40-7.78 (m, 3H), 4.89 (br. s., 1H), 4.51-4.65 (m, 1H), 4.07 (dd,J=3.26, 11.55 Hz, 1H), 3.37-3.50 (m, 1H), 2.86-3.05 (m, 1H), 2.49-2.64(m, 1H), 2.35-2.48 (m, 1H), 1.86-2.33 (m, 10H), 1.65-1.80 (m, 2H),1.46-1.63 (m, 3H), 1.27-1.42 (m, 2H), 0.98 (d, J=6.27 Hz, 3H), 0.79 (t,J=7.28 Hz, 3H); LCMS m/z 486.1 [M+H]+

Example 1429-((6-((cis-4-trifluoromethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 83.¹H NMR (400 MHz, METHANOL-d₄) δ 7.97-8.07 (m, 1H), 7.80-7.93 (m, 2H),7.53-7.66 (m, 1H), 7.31-7.38 (m, 1H), 7.20-7.30 (m, 1H), 4.88-4.94 (m,1H), 4.59-4.74 (m, 2H), 3.55-3.74 (m, 2H), 3.36-3.46 (m, 1H), 2.47-2.71(m, 2H), 1.99-2.37 (m, 9H), 1.56-1.95 (m, 8H); LCMS m/z 476.1 [M+H]+

Example 143 methyl2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-(7R,9aR)-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, CHLOROFORM-d) δ 8.27 (d, J=8.53 Hz, 1H), 7.89-8.02 (m,2H), 7.52 (dd, J =1.76, 9.04 Hz, 1H), 7.35 (d, J=9.29 Hz, 1H), 4.88 (br.s., 1H), 4.16-4.39 (m, 2H), 3.75 (s, 3H), 3.65 (d, J=11.80 Hz, 1H),3.36-3.55 (m, 2H), 3.07-3.32 (m, 5H), 2.68-2.84 (m, 2H), 2.35 (d,J=12.30 Hz, 1H), 2.05-2.28 (m, 3H), 1.52-1.97 (m, 9H); LCMS m/z 573.3[M+H]⁺

Example 1443-(4-{[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]oct-1-yl)-carboxylicacid

The title compound was prepared according to the method of Example 86.¹H NMR (400 MHz, DMSO-d₆) δ 12.29 (br. s., 1H), 8.84 (br. s., 1H), 8.22(d, J=9.29 Hz, 1H), 8.06-8.16 (m, 2H), 7.65-7.76 (m, 2H), 5.10 (br. s.,1H), 4.23 (br. s., 2H), 2.39-2.47 (m, 1H), 2.04 (d, J=12.80 Hz, 2H),1.88 (s, 12H), 1.53-1.78 (m, 7H); LCMS m/z 544.2 [M+H]+

Example 1452-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-(7R,9aR)-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (d, J=8.53 Hz, 1H), 7.89-8.02 (m,2H), 7.52 (d, J =8.78 Hz, 1H), 7.35 (d, J=9.29 Hz, 1H), 4.89 (br. s.,1H), 4.18-4.41 (m, 2H), 3.22-3.74 (m, 6H), 2.87 (br. s., 1H), 2.67 (s,1H), 2.03-2.37 (m, 5H), 1.55-1.96 (m, 10H); LCMS m/z 559.3 [M+H]⁺

Example 1462-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (dd, J=2.89, 9.41 Hz, 1H), 8.02-8.18(m, 2H), 7.61-7.79 (m, 2H), 5.11 (br. s., 1H), 4.45 (d, J=5.52 Hz, 1H),4.27-4.39 (m, 2H), 3.89-4.24 (m, 2H), 3.13 (br. s., 1H), 2.74-3.00 (m,1H), 2.27-2.46 (m, 4H), 1.97-2.11 (m, 2H), 1.81-1.91 (m, 1H), 1.54-1.80(m, 6H); LCMS m/z 516.2 [M+H]⁺

Example 147N-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-amino-indane-5-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (br. s., 2H), 8.30 (s, 1H), 8.22 (d,J=9.29 Hz, 1H), 8.08-8.16 (m, 2H), 7.96 (dd, J=1.13, 7.91 Hz, 1H), 7.77(dd, J=1.76, 9.04 Hz, 1H), 7.69 (d, J=9.54 Hz, 1H), 7.49 (d, J=8.03 Hz,1H), 5.11 (br. s., 1H), 4.94 (br. s., 1H), 4.30-4.55 (m, 2H), 3.13-3.29(m, 1H), 2.90-3.08 (m, 1H), 2.55-2.70 (m, 1H), 2.30-2.45 (m, 2H), 2.04(d, J=12.80 Hz, 2H), 1.54-1.81 (m, 6H); LCMS m/z 552.2 [M+H]³⁰

Example 1483-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-6-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, DMSO-d₆) δ 9.75-9.97 (m, 1H), 8.22 (d, J=9.29 Hz, 1H),8.10 (d, J=12.55 Hz, 2H), 7.71 (d, J=9.29 Hz, 2H), 5.12 (br. s., 1H),4.52 (br. s., 2H), 3.58 (br. s., 4H), 2.36-2.46 (m, 1H), 2.21 (br. s.,2H), 1.89-2.11 (m, 3H), 1.52-1.81 (m, 6H); LCMS m/z 502.2 [M+H]⁺

Example 1492-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-azaspiro[3.2]hexane-5-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.27 (d, J=8.53 Hz, 1H), 8.15 (d, J=9.29Hz, 1H), 8.03 (s, 1H), 7.54-7.67 (m, 2H), 5.02 (br. s., 1H), 4.62 (br.s., 2H), 4.04-4.52 (m, 4H), 2.08-2.37 (m, 3H), 1.99 (dd, J=5.77, 9.04Hz, 1H), 1.65-1.90 (m, 6H), 1.41 (dd, J=5.52, 9.04 Hz, 1H), 1.23-1.35(m, 1H); LCMS m/z 502.2 [M+H]⁺

Example 150N-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-decahydroisoquinoline-8-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.27 (d, J=8.53 Hz, 1H), 8.15 (d, J=9.29Hz, 1H), 8.04 (s, 1H), 7.57-7.71 (m, 2H), 5.03 (br. s., 1H), 4.40-4.59(m, 2H), 3.36 (br. s., 1H), 3.09-3.28 (m, 2H), 2.52-2.74 (m, 2H), 2.28(d, J=8.03 Hz, 1H), 2.17 (d, J=12.05 Hz, 2H), 1.89-2.10 (m, 3H),1.69-1.88 (m, 10H), 1.35-1.55 (m, 3H); LCMS m/z 558.2 [M+H]⁺

Example 1513-((6-((cis-4-trifluoromethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.28 (d, J=7.53 Hz, 1H), 8.17 (d, J=9.29Hz, 1H), 8.05-8.12 (m, 1H), 7.71 (ddd, J=1.63, 9.10, 13.62 Hz, 1H), 7.60(d, J=9.29 Hz, 1H), 5.03 (br. s., 1H), 4.48 (d, J=14.31 Hz, 2H),3.37-3.69 (m, 4H), 2.50-2.80 (m, 3H), 2.11-2.38 (m, 3H), 1.61-2.05 (m,12H); LCMS m/z 544.2 [M+H]⁺

Example 152N-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-4-aminobicyclo[2.2.1]heptane-1-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.27 (d, J=8.53 Hz, 1H), 8.14 (d, J=9.29Hz, 1H), 8.04 (d, J=1.25 Hz, 1H), 7.67 (dd, J=2.01, 9.04 Hz, 1H), 7.59(d, J=9.29 Hz, 1H), 5.02 (br. s., 1H), 4.40 (s, 2H), 2.14-2.36 (m, 5H),1.96-2.13 (m, 6H), 1.86-1.95 (m, 2H), 1.68-1.86 (m, 6H); LCMS m/z 530.2[M+H]⁺

Example 153N-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-1-aminoadamantane-3-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.22-8.31 (m, 1H), 8.10-8.18 (m, 1H),8.03 (d, J=1.51 Hz, 1H), 7.63-7.70 (m, 1H), 7.54-7.62 (m, 1H), 5.01 (br.s., 1H), 4.37 (s, 2H), 2.39 (br. s., 2H), 2.27 (td, J=7.69, 11.23 Hz,1H), 2.12-2.21 (m, 4H), 1.96-2.11 (m, 6H), 1.65-1.94 (m, 10H); LCMS m/z570.3 [M+H]⁺

Example 1543-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-3-azabicyclo[3.3.0]octane-7-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.27 (d, J=9.04 Hz, 1H), 8.15 (d, J=9.29Hz, 1H), 8.04 (br. s., 1H), 7.53-7.72 (m, 2H), 5.02 (br. s., 1H), 4.51(d, J=2.76 Hz, 2H), 3.72 (br. s., 1H), 3.37-3.59 (m, 1H), 2.73-3.25 (m,5H), 2.08-2.38 (m, 4H), 1.55-2.05 (m, 9H); LCMS m/z 530.2 [M+H]⁺

Example 1552-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-((9S,9aR)-octahydro-1H-pyrido[1,2-a]pyrazin-9-yl)methanol

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.17 (d, J=7.53 Hz, 1H), 8.06 (d, J=9.29Hz, 1H), 7.86 (br. s., 1H), 7.58-7.69 (m, 1H), 7.51 (d, J=9.29 Hz, 1H),4.98 (br. s., 1H), 3.65-4.03 (m, 3H), 3.37-3.64 (m, 3H), 3.06-3.22 (m,3H), 2.91-3.05 (m, 1H), 2.52-2.89 (m, 1H), 2.07-2.45 (m, 4H), 1.64-2.04(m, 11H); LCMS m/z 545.3 [M+H]⁺

Example 1568-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 98.¹H NMR (400 MHz, METHANOL-d₄) δ 8.25-8.33 (m, 1H), 8.18 (d, J=9.29 Hz,1H), 8.09 (d, J=1.26 Hz, 1H), 7.69-7.76 (m, 1H), 7.61-7.68 (m, 1H), 4.98(br. s., 1H), 4.36 (s, 2H), 4.03 (br. s., 2H), 2.89-3.06 (m, 1H),2.43-2.60 (m, 2H), 1.87-2.29 (m, 14H); LCMS m/z 545.3 [M+H]⁺

Example 1572-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-2-aza-6-oxaspiro[3.4]octane-7-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.26 (d, J=8.53 Hz, 1H), 8.15 (d, J=9.04Hz, 1H), 8.02 (d, J=1.51 Hz, 1H), 7.55-7.66 (m, 2H), 5.02 (br. s., 1H),4.46-4.62 (m, 3H), 3.98-4.44 (m, 6H), 2.58-2.70 (m, 1H), 2.45 (dd,J=5.15, 13.43 Hz, 1H), 2.07-2.36 (m, 3H), 1.65-1.90 (m, 6H); LCMS m/z532.2 [M+H]⁺

Example 158(1R,5S,7r)-3-((2-(4-(trifluoromethyl)cyclohexyloxy)-1-(trifluoromethyl)naphthalen-6-yl)methyl)-3-aza-bicyclo[3.3.1]nonane-7-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.28 (d, J=8.78 Hz, 1H), 8.16 (d, J=9.29Hz, 1H), 8.04-8.10 (m, 1H), 7.66-7.75 (m, 1H), 7.60 (d, J=9.29 Hz, 1H),5.03 (br. s., 1H), 4.46 (s, 2H), 3.35-3.74 (m, 3H), 2.87-3.26 (m, 2H),2.03-2.53 (m, 7H), 1.68-1.96 (m, 10H); LCMS m/z 544.2 [M+H]⁺

Example 159N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-3-(azetidine-3-yl)-cyclohexane-1-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.26 (d, J=8.78 Hz, 1H), 8.15 (d, J=9.29Hz, 1H), 8.02 (s, 1H), 7.55-7.65 (m, 2H), 5.02 (br. s., 1H), 4.39-4.63(m, 2H), 3.93-4.30 (m, 4H), 2.52-2.79 (m, 1H), 2.08-2.37 (m, 4H),1.52-2.06 (m, 11H), 1.13-1.50 (m, 2H), 0.98 (q, J=12.30 Hz, 1H),0.75-0.90 (m, 1H); LCMS m/z 558.3 [M+H]⁺

Example 1608-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)quinolin-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 101.¹H NMR (400 MHz, METHANOL-d₄) δ 8.67 (d, J=9.04 Hz, 1H), 8.34 (d, J=9.54Hz, 1H), 7.85 (d, J=9.54 Hz, 1H), 7.60 (d, J=9.04 Hz, 1H), 5.07 (br. s.,1H), 4.60 (s, 2H), 4.25 (br. s., 2H), 3.05 (tt, J=5.80, 12.14 Hz, 1H),2.08-2.55 (m, 11H), 1.68-1.89 (m, 6H); LCMS m/z 531.2 [M+H]⁺

Example 1612-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-2-aza-5-oxaspiro[5.4]decane-8-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 1.63-2.39 (m, 14H) 2.87-3.08 (m, 1H)3.21 (br. s., 2H) 3.34-3.47 (m, 1H) 3.80-3.98 (m, 2H) 4.51 (s, 2H) 5.03(br. s., 1H) 7.61 (d, J=9.29 Hz, 1H) 7.68 (dd, J=9.04, 1.76 Hz, 1H) 8.07(s, 1H) 8.16 (d, J=9.29 Hz, 1H) 8.29 (d, J=8.53 Hz, 1H); LCMS m/z 560.2[M+H]⁺

Example 162N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-8-aminobicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 1

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.28 (d, J=8.28 Hz, 1H), 8.15 (d, J=9.29Hz, 1H), 8.08 (d, J=1.51 Hz, 1H), 7.71 (dd, J=1.76, 9.04 Hz, 1H), 7.59(d, J=9.29 Hz, 1H), 5.02 (br. s., 1H), 4.47 (s, 2H), 2.81 (tt, J=6.24,11.95 Hz, 1H), 2.49 (br. s., 2H), 2.10-2.35 (m, 3H), 1.63-1.97 (m, 15H);LCMS m/z 544.2 [M+H]⁺

Example 163N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-8-aminobicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 2

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.27 (d, J=8.53 Hz, 1H), 8.14 (d, J=9.29Hz, 1H), 8.06 (d, J=1.51 Hz, 1H), 7.69 (dd, J=1.76, 9.04 Hz, 1H), 7.59(d, J=9.54 Hz, 1H), 5.02 (br. s., 1H), 4.43 (s, 2H), 2.54-2.76 (m, 3H),2.10-2.37 (m, 3H), 1.59-2.06 (m, 15H); LCMS m/z 544.2 [M+H]⁺

Example 164N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-1-amino-3,5-dimethyladamantane

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.27 (d, J=8.28 Hz, 1H), 8.14 (d, J=9.29Hz, 1H), 8.02 (d, J=1.51 Hz, 1H), 7.65 (dd, J=1.88, 9.16 Hz, 1H), 7.59(d, J=9.29 Hz, 1H), 5.02 (br. s., 1H), 4.34 (s, 2H), 2.32-2.42 (m, 1H),2.13-2.22 (m, 2H), 1.62-1.95 (m, 13H), 1.39-1.55 (m, 4H), 1.23-1.36 (m,2H), 0.95-1.04 (m, 6H); LCMS m/z 554.3 [M+H]⁺

Example 1657-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-azabicyclo[2.2.1]heptane-2-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.30 (d, J=8.78 Hz, 1H), 8.17 (d, J=9.29Hz, 1H), 8.09 (d, J=2.76 Hz, 1H), 7.71 (dd, J=2.01, 9.04 Hz, 1H), 7.61(d, J=9.29 Hz, 1H), 5.03 (br. s., 1H), 4.39-4.60 (m, 2H), 4.28-4.37 (m,1H), 4.14 (br. s., 1H), 3.34-3.91 (m, 1H), 2.56-2.71 (m, 1H), 2.45 (br.s., 1H), 2.12-2.37 (m, 4H), 1.99-2.11 (m, 1H), 1.91-1.98 (m, 1H),1.68-1.89 (m, 7H); LCMS m/z 516.2 [M+H]⁺

Example 166N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-aminobicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.28 (d, J=8.53 Hz, 1H), 8.15 (d, J=9.29Hz, 1H), 8.08 (d, J=1.26 Hz, 1H), 7.71 (dd, J=2.01, 9.04 Hz, 1H), 7.60(d, J=9.29 Hz, 1H), 5.02 (br. s., 1H), 4.45 (s, 2H), 3.18-3.25 (m, 1H),2.59-2.71 (m, 1H), 2.04-2.38 (m, 9H), 1.59-1.90 (m, 10H), 1.36-1.56 (m,2H); LCMS m/z 558.3 [M+H]⁺

Example 1679-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-aza-7-oxabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.29 (d, J=8.78 Hz, 1H), 8.10-8.21 (m,2H), 7.74 (dd, J=1.76, 9.04 Hz, 1H), 7.61 (d, J=9.29 Hz, 1H), 5.03 (br.s., 1H), 4.82 (br. s., 2H), 4.10 (br. s., 2H), 3.70-3.86 (m, 1H), 3.55(br. s., 2H), 2.04-2.88 (m, 8H), 1.58-1.90 (m, 7H); LCMS m/z 558.3[M+H]⁺

Example 1689-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-azabicyclo[3.3.1]nonane

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.28 (d, J=8.53 Hz, 1H), 8.10-8.19 (m,2H), 7.75 (dd, J=2.01, 9.04 Hz, 1H), 7.60 (d, J=9.29 Hz, 1H), 5.03 (br.s., 1H), 4.71 (s, 2H), 3.53 (br. s., 2H), 2.47-2.63 (m, 2H), 1.96-2.37(m, 9H), 1.62-1.95 (m, 10H); LCMS m/z 500.2 [M+H]⁺

Example 1699-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-hydroxy-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.29 (d, J=8.53 Hz, 1H), 8.08-8.21 (m,2H), 7.74 (dd, J=1.51, 9.04 Hz, 1H), 7.60 (d, J=9.29 Hz, 1H), 5.03 (br.s., 1H), 4.41-4.73 (m, 3H), 3.98-4.34 (m, 1H), 3.69 (br. s., 2H), 2.79(d, J=15.81 Hz, 1H), 2.50 (br. s., 1H), 1.65-2.37 (m, 15H); LCMS m/z560.2 [M+H]⁺

Example 1709-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-oxo-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.31 (d, J=7.53 Hz, 1H), 8.13-8.21 (m,2H), 7.79 (dd, J=2.01, 9.04 Hz, 1H), 7.61 (d, J=9.29 Hz, 1H), 5.03 (br.s., 1H), 4.11 (br. s., 2H), 3.36 (d, J=3.26 Hz, 1H), 2.60-2.77 (m, 3H),2.08-2.46 (m, 7H), 1.65-1.91 (m, 6H); LCMS ml/z 558.0 [M+H]⁺

Example 1719-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 97.¹H NMR (400 MHz, METHANOL-d₄) δ 8.26 (d, J=8.53 Hz, 1H), 8.08-8.16 (m,2H), 7.73 (d, J=9.04 Hz, 1H), 7.57 (d, J=9.54 Hz, 1H), 4.95 (br. s.,1H), 4.58-4.77 (m, 2H), 3.65 (d, J=12.55 Hz, 2H), 3.35-3.51 (m, 1H),2.57 (d, J=8.53 Hz, 2H), 1.98-2.40 (m, 8H), 1.90 (dd, J=5.65, 14.43 Hz,1H), 1.52-1.79 (m, 5H), 1.22-1.51 (m, 5H), 0.85-0.99 (m, 3H); LCMS m/z504.1 [M+H]⁺

Example 1728-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 97.¹H NMR (400 MHz, METHANOL-d₄) δ 8.27 (d, J=8.28 Hz, 1H), 8.02-8.18 (m,2H), 7.69 (dd, J=1.76, 9.04 Hz, 1H), 7.58 (d, J=9.29 Hz, 1H), 4.95 (br.s., 1H), 4.35 (s, 2H), 4.02 (br. s., 2H), 2.88-3.06 (m, 1H), 2.42-2.60(m, 2H), 1.96-2.25 (m, 8H), 1.20-1.77 (m, 9H), 0.93 (t, J=7.15 Hz, 3H);LCMS m/z 490.1 [M+H]³⁰

Example 1738-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 1

The title compound was prepared according to the method of Example 88.¹H NMR (400 MHz, METHANOL-d₄) δ 8.32 (d, J=8.78 Hz, 1H), 8.15 (d, J=9.29Hz, 1H), 8.04 (s, 1H), 7.73 (dd, J=1.38, 9.16 Hz, 1H), 7.61 (d, J=9.29Hz, 1H), 5.03 (br. s., 1H), 4.50-4.61 (m, 1H), 4.40 (q, J=6.53 Hz, 1H),3.47 (d, J=6.27 Hz, 1H), 2.88-3.05 (m, 1H), 2.47-2.62 (m, 1H), 2.08-2.41(m, 7H), 1.65-2.06 (m, 12H); LCMS m/z 544.0 [M+H]⁺

Example 1748-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 2

The title compound was prepared according to the method of Example 88.¹H NMR (400 MHz, METHANOL-d₄) δ 8.32 (d, J=8.78 Hz, 1H), 8.01-8.20 (m,2H), 7.73 (dd, J=1.76, 9.04 Hz, 1H), 7.61 (d, J=9.29 Hz, 1H), 5.03 (br.s., 1H), 4.50-4.61 (m, 1H), 4.40 (q, J=6.53 Hz, 1H), 3.47 (d, J=6.27 Hz,1H), 2.95 (tt, J=6.09, 11.73 Hz, 1H), 2.47-2.62 (m, 1H), 2.07-2.44 (m,7H), 1.64-2.05 (m, 12H); LCMS m/z 544.0 [M+H]⁺

Example 1759-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 93.¹H NMR (400 MHz, METHANOL-d₄) δ 8.30 (d, J=9.04 Hz, 1H), 8.04-8.19 (m,2H), 7.77 (d, J=9.29 Hz, 1H), 7.58 (d, J=9.29 Hz, 1H), 5.00-5.28 (m,1H), 4.95 (br. s., 1H), 4.20 (d, J=12.05 Hz, 1H), 3.38 (dd, J=6.02,11.80 Hz, 1H), 3.17 (d, J=14.31 Hz, 1H), 2.29-2.62 (m, 3H), 1.52-2.28(m, 16H), 1.23-1.51 (m, 5H), 0.93 (t, J=7.15 Hz, 3H); LCMS m/z 518.1[M+H]⁺

Example 1768-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 93.¹H NMR (400 MHz, METHANOL-d₄) δ 8.20 (d, J=8.53 Hz, 1H), 8.02 (d, J=9.29Hz, 1H), 7.92 (d, J=1.25 Hz, 1H), 7.61 (dd, J=1.76, 9.04 Hz, 1H), 7.49(d, J=9.29 Hz, 1H), 4.85 (br. s., 1H), 4.40-4.51 (m, 1H), 4.29 (q,J=6.53 Hz, 1H), 3.29-3.43 (m, 1H), 2.76-2.94 (m, 1H), 2.36-2.52 (m, 1H),1.77-2.31 (m, 9H), 1.66-1.75 (m, 3H), 1.43-1.65 (m, 4H), 1.13-1.42 (m,5H), 0.83 (t, J=7.15 Hz, 3H); LCMS m/z 504.1 [M+H]⁺

Example 1779-(1-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 88.¹H NMR (400 MHz, METHANOL-d₄) δ 8.34 (d, J=7.53 Hz, 1H), 8.04-8.22 (m,2H), 7.76 (d, J=8.53 Hz, 1H), 7.62 (d, J=9.29 Hz, 1H), 5.03 (br. s.,1H), 4.93 (dd, J=3.39, 11.42 Hz, 1H), 4.26 (d, J=12.05 Hz, 1H),3.35-3.46 (m, 1H), 3.06-3.20 (m, 1H), 1.54-2.63 (m, 21H), 0.75 (t,J=7.15 Hz, 3H); LCMS m/z 572.1 [M+H]⁺

Example 1788-(1-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 88.¹H NMR (400 MHz, METHANOL-d₄) δ 8.34 (d, J=8.78 Hz, 1H), 8.15 (d, J=9.29Hz, 1H), 8.03 (s, 1H), 7.69 (d, J=9.04 Hz, 1H), 7.62 (d, J=9.29 Hz, 1H),5.03 (br. s., 1H), 4.58 (d, J=6.02 Hz, 1H), 4.09 (dd, J=2.89, 11.42 Hz,1H), 3.41 (d, J=2.76 Hz, 1H), 2.86-3.03 (m, 1H), 1.65-2.62 (m, 19H),0.78 (t, J=7.28 Hz, 3H); LCMS m/z 558.0 [M+H]⁺

Example 1799-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 92.¹H NMR (400 MHz, METHANOL-d₄) δ 8.32 (d, J=7.53 Hz, 1H), 8.12 (d, J=9.29Hz, 2H), 7.74 (d, J=8.28 Hz, 1H), 7.59 (d, J=9.29 Hz, 1H), 4.89-5.01 (m,2H), 4.24 (br. s., 1H), 3.35-3.45 (m, 1H), 3.05-3.23 (m, 1H), 1.82-2.61(m, 13H), 1.52-1.80 (m, 5H), 1.23-1.52 (m, 5H), 0.93 (t, J=7.15 Hz, 3H),0.76 (t, J=7.28 Hz, 3H); LCMS m/z 532.1 [M+H]⁺

Example 1808-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 92.¹H NMR (400 MHz, METHANOL-d₄) δ 8.32 (d, J=8.53 Hz, 1H), 8.12 (d, J=9.29Hz, 1H), 7.98-8.09 (m, 1H), 7.67 (dd, J=1.63, 9.16 Hz, 1H), 7.60 (d,J=9.29 Hz, 1H), 4.96 (br. s., 1H), 4.58 (d, J=6.27 Hz, 1H), 4.09 (dd,J=3.26, 11.55 Hz, 1H), 3.37-3.46 (m, 1H), 2.85-3.05 (m, 1H), 1.86-2.63(m, 12H), 1.54-1.76 (m, 4H), 1.38-1.52 (m, 2H), 1.25-1.37 (m, 3H), 0.93(t, J=7.15 Hz, 3H), 0.78 (t, J=7.28 Hz, 3H); LCMS m/z 518.1 [M+H]⁺

Example 1818-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d₄) δ 8.26-8.32 (m, 1H), 8.12-8.21 (m, 2H),7.76 (dd, J=2.01, 9.04 Hz, 1H), 7.60 (d, J=9.04 Hz, 1H), 5.03 (br. s.,1H), 4.71 (br. s., 2H), 3.65 (br. s., 2H), 3.35-3.45 (m, 1H), 1.62-2.75(m, 19H); LCMS m/z 544.2 [M+H]⁺

Example 1829-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-chloronaphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 94.¹H NMR (400 MHz, METHANOL-d₄) δ 8.33 (d, J=9.06 Hz, 1H), 8.08 (d, J=4.91Hz, 1H), 7.88 (d, J=9.06 Hz, 1H), 7.78 (d, J=8.69 Hz, 1H), 7.52 (d,J=9.06 Hz, 1H), 5.00-5.31 (m, 1H), 4.88 (br. s., 1H), 4.18 (br. s., 1H),3.35-3.48 (m, 1H), 3.08-3.21 (m, 1H), 1.43-2.67 (m, 21H), 1.20-1.42 (m,3H), 0.93 (t, J=7.18 Hz, 3H); LCMS m/z 484.1 [M+H]⁺

Example 1839-((5-Chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 110.¹H NMR (400 MHz, METHANOL-d₄) δ 8.30 (d, J=9.06 Hz, 1H), 8.09 (s, 1H),7.90 (d, J=9.06 Hz, 1H), 7.73 (d, J=9.06 Hz, 1H), 7.52 (d, J=9.06 Hz,1H), 4.87-4.91 (m, 1H), 4.59-4.77 (m, 2H), 3.61-3.70 (m, 2H), 3.35-3.46(m, 1H), 2.48-2.75 (m, 2H), 1.80-2.36 (m, 9H), 1.42-1.78 (m, 8H), 0.97(d, J=4.91 Hz, 3H); LCMS m/z 456.0 [M+H]⁺

Example 1848-(1-(5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 110.¹H NMR (400 MHz, METHANOL-d₄) δ 8.33 (d, J=9.04 Hz, 1H), 7.99 (s, 1H),7.88 (d, J=9.04 Hz, 1H), 7.71 (dd, J=1.51, 9.04 Hz, 1H), 7.53 (d, J=9.04Hz, 1H), 4.88 (br. s., 1H), 4.54 (d, J=6.27 Hz, 1H), 4.40 (q, J=6.53 Hz,1H), 3.38-3.53 (m, 1H), 2.95 (tt, J=5.93, 11.76 Hz, 1H), 2.46-2.63 (m,1H), 1.75-2.37 (m, 12H), 1.45-1.73 (m, 6H), 1.23-1.39 (m, 3H), 0.93 (t,J=7.15 Hz, 3H); LCMS m/z 470.0 [M+H]

Example 185

8-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 110.¹H NMR (400 MHz, METHANOL-d₄) δ 8.30 (d, J=8.78 Hz, 1H), 8.04 (s, 1H),7.90 (d, J=9.04 Hz, 1H), 7.70 (dd, J=1.51, 8.78 Hz, 1H), 7.52 (d, J=9.04Hz, 1H), 4.88 (br. s., 1H), 4.36 (s, 2H), 4.02 (br. s., 2H), 2.97 (t,J=6.02 Hz, 1H), 2.42-2.63 (m, 2H), 1.97-2.24 (m, 8H), 1.43-1.73 (m, 6H),1.20-1.39 (m, 3H), 0.93 (t, J=7.28 Hz, 3H); LCMS m/z 456.1 [M+H]⁺

Example 1868-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

Step 1: methyl 6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate

A mixture of methyl 6-hydroxy-2-naphthoate (14.0 g, 70.0 mmol, 1.0 eq),cis-4-(trifluoromethyl)cyclohexyl methanesulfonate (21.0 g, 84.0 mmol,1.2 eq) and Cs₂CO₃ (45.0 g, 140.0 mmol, 2.0 eq) in DMF (150 mL) washeated at 80° C. for 16 h and cooled down. The mixture was diluted withEtOAc (300 mL) and washed with H₂O (300 mL×3). The organic layer wasdried over Na₂SO₄ and concentrated to yield a crude product, which waspurified by column chromatography on silica gel (petroleum ether aseluent) to give methyl6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate as yellow solid(13.0 g, yield: 65%). ¹H NMR (400 MHz, CDCl₃) δ: 8.52 (s, 1H), 8.01 (d,J=8.8 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.22 (dd,J=2.4 Hz, 8.8 Hz, 1H), 7.16 (s, 1H), 4.76 (s, 1H), 3.96 (s, 3H),2.27-2.11 (m, 3H), 1.85-1.78 (m, 4H), 1.65-1.59 (m, 2H). LCMS m/z 353.1[M+H]⁺

Step 2: methyl5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate

To a mixture of methyl6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate (1.75 g, 5.0mmol, 1.0 eq) and NCS (1.05 g, 7.5 mmol, 1.5 eq) in MeCN (10 mL) wasadded TFA (170 mg, 1.5 mmol, 0.3 eq). The mixture was stirred at rt for16 h and quenched with aq. Na₂SO₃ (50 mL). The mixture was extractedwith EtOAc (50 mL×2). The organic layers were dried over Na₂SO₄ andconcentrated to yield a crude product, which was purified by columnchromatography on silica gel (petroleum ether/EtOAc=50:1) to give methyl5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate as ayellow solid (900 mg, yield: 50%). LCMS m/z 387.1 [M+H]⁺

Step 3:8-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 105.¹H NMR (400 MHz, METHANOL-d₄) δ: 8.15 (d, J=8.8 Hz, 1H), 7.92 (s, 1H),7.82 (d, J=9.6 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.38 (d, J=9.6 Hz, 1H),4.80 (s, 1H), 4.76-4.72 (m, 1H), 4.11-4.08 (m, 1H), 2.95-2.84 (m, 1H),2.18-1.96 (m, 6H), 1.88-1.55 (m, 11H). LCMS m/z 510.1 [M+H]⁺

Example 187 8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

Step 1: methyl5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate

A mixture of methyl5-iodo-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate (2.4 g,5.0 mmol, 1.0 eq), Zn(CN)₂ (870 mg, 7.5 mmol, 1.5 eq) and TEA (1.3 g,12.5 mmol, 2.5 eq) in DMA (15 mL) was purged with N₂ for 3 times, thenPd(dppf)Cl₂·DCM (410 mg, 0.5 mmol, 0.1 eq) was added. The mixture wasstirred at 130° C. for 16 h and cooled down. The mixture was dilutedwith EtOAc (150 mL) and washed with H₂O (100 mL×3). The organic layerwas dried over Na₂SO₄ and concentrated to yield a crude product, whichwas purified by column chromatography on silica gel (petroleumether/EtOAc=10:1) to give methyl5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate as ayellow solid (900 mg, yield: 50%). LCMS m/z 378.1 [M+H]⁺

Step 2: 8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 105.¹H NMR (400 MHz, CD₃OD) δ: 8.28 (d, J=9.2 Hz, 1H), 8.11-8.09 (m, 2H),7.78 (d, J=10.0 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 5.09 (s, 1H), 4.22-4.18(m, 1H), 3.05-2.96 (m, 1H), 2.32-1.83 (m, 18H). LCMS m/z 501.2 [M+H]⁺

Example 1888-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

Step 1: 5-iodo-6-((cis-4-methylcyclohexyl)oxy)-2-naphthaldehyde

The title compound was prepared according to the method of Example 84.LCMS m/z 395.1 [M+H]⁺

Step 2: methyl8-((5-iodo-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylate

Into a mixture of5-iodo-6-((cis-4-methylcyclohexyl)oxy)-2-naphthaldehyde (130 mg, 0.33mmol, 1.0 eq), TEA (50 mg, 0.50 mmol, 1.5 eq) and methyl8-azabicyclo[3.2.1]octane-3-carboxylate (62 mg, 0.36 mmol, 1.1 eq) inTHF (2 mL) was added Ti(OiPr)₄ (188 mg, 0.66 mmol, 2.0 eq). The mixturewas stirred at 100° C. for 2 h and cooled down. NaBH(OAc)₃ (140 mg, 0.66mmol, 2.0 eq) was added, and the mixture was stirred at 100° C. foradditional 2 h. The mixture was diluted with water (10 mL) and extractedwith EtOAc (10 mL×2). The combined organic layers were washed with water(10 mL), brine (10 mL), dried over Na₂SO₄ and concentrated. The residuewas purified by reversed phase HPLC (MeCN/H₂O-0.05% TFA) to give methyl8-((5-iodo-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylateas a yellow solid (130 mg, yield: 92%). LCMS m/z 548.2 [M+H]⁺

Step 3: methyl8-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylate

Into a mixture of methyl8-((5-iodo-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylate(130 mg, 0.24 mmol, 1.0 eq), Zn(CN)₂ (55 mg, 0.48 mmol, 2.0 eq) andX-phos (23 mg, 0.048 mmol, 0.2 eq) in DMF (3 mL) was added Pd₂(dba)₃ (22mg, 0.024 mmol, 0.1 eq). The mixture was stirred at 100° C. for 16 hunder N₂ atmosphere. After cooling to rt, the mixture was filtrated andthe filtrate was purified by reversed phase HPLC (MeCN/H2O-0.05% TFA) togive methyl8-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylateas a yellow solid (40 mg, yield: 37%). LCMS m/z 447.3 [M+H]⁺

Step 4:8-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

Into a solution of methyl8-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylate(40 mg, 0.09 mmol, 1.0 eq) in MeOH (3 mL) was added NaOH (7 mg, 0.18mmol, 2.0 eq) and H₂O (0.5 mL). The reaction mixture was stirred at 80°C. for 1 h. Then the reaction was cooled to rt, and acidified with 1NHCl to pH=6. The mixture was directly purified by reversed phase HPLC(MeCN/H2O-0.05% TFA) to give8-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid as a white solid (17 mg, yield: 44%). ¹H NMR (400 MHz, CD3OD) δ:8.21 (d, J=9.2 Hz, 1H), 8.11-8.09 (m, 2H), 7.82 (d, J=8.8 Hz, 1H), 7.57(d, J=9.2 Hz, 1H), 5.02 (s, 1H), 4.27 (s, 2H), 3.85-3.81 (m, 2H),2.70-2.64 (m, 1H), 2.40-2.38 (m, 2H), 2.09-2.02 (m, 6H), 1.96-1.92 (m,2H), 1.77-1.72 (m, 2H), 1.59-1.56 (m, 5H), 1.01 (d, J=7.2 Hz, 3H). LCMSm/z 433.3 [M+H]⁺

Example 189 8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

Step 1: 6-Acetyl-2-((cis-4-methylcyclohexyl)oxy)-1-naphthonitrile

To a mixture of1-(5-iodo-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethanone (690mg, 1.69 mmol, 1.0 eq), CuCN (226 mg, 2.54 mmol, 1.5 eq), TEA (342 mg,3.38 mmol, 2.0 eq) and (o-tolyl)₃P (103 mg, 0.34 mmol, 0.2 eq) in DMF (4mL) was added Pd₂(dba)₃ (155 mg, 0.17 mmol, 0.1 eq). The mixture wasstirred at 100° C. for 16 h under N₂ atmosphere. After cooling to rt,the mixture was diluted with EtOAc (30 mL) and washed with H₂O (15mL×3). The organic phase was dried and concentrated. The residue waspurified by column chromatography on silica gel (petroleumether/EtOAc=10:1) to give6-Acetyl-2-((cis-4-methylcyclohexyl)oxy)-1-naphthonitrile as a yellowsolid (270 mg, yield: 52%). LCMS m/z 308.2 [M+H]⁺

Step 2: 8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 102.¹H NMR (400 MHz, METHANOL-d₄) δ: 8.20 (d, J=9.2 Hz, 1H), 8.13 (d, J=8.4Hz, 1H), 8.10 (s, 1H), 7.86 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.58 (d, J=9.2Hz, 1H), 5.01 (s, 1H), 4.50-4.44 (m, 1H), 4.25-4.20 (m, 1H), 3.58-3.53(m, 1H), 2.71-2.64 (m, 1H), 2.41-2.35 (m, 1H), 2.27-2.20 (m, 2H),2.08-1.96 (m, 6H), 1.86-1.71 (m, 6H), 1.58-1.54 (m, 5H), 0.99 (d, J=7.2Hz, 3H). LCMS m/z 447.3 [M+H]⁺

Example 1908-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

Step 1: methyl5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoate

To a solution of methyl 6-amino-2-naphthoate (2.5 g, 12.4 mmol, 1.0 eq),4-(trifluoromethyl)cyclohexanone (3.1 g, 18.6 mmol, 1.5 eq) and HOAc(744 mg, 12.4 mmol, 1.0 eq) in DCE (50 mL) was added NaBH(OAc)₃ (5.2 g,25.0 mmol, 2.0 eq) portionwise. The mixture was stirred at 90° C. for 20h. Water (100 mL) was added and the mixture was extracted with DCM (50mL×3). The organic phase was dried and concentrated. The residue waspurified by column chromatography on silica (petroleum ether/EtOAc=5:1)to afford methyl6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoate (1.1 g, yield26%) and methyl6-(((trans)-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoate (1.2 g,yield 27%) as yellow solid.

cis isomer: ¹H NMR (400 MHz, CDCl₃) δ: 8.04 (s, 1H), 7.93 (dd, J=2.0 Hz,8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 6.94 (dd,J=2.4 Hz, 8.8 Hz, 1H), 6.80 (s, 1H), 3.94 (s, 3H), 3.82 (s, 1H),2.35-2.05 (m, 3H), 1.83-1.65 (m, 6H). LCMS m/z 352.1 [M+H]⁺.

trans isomer: ¹H NMR (400 MHz, CDCl₃) δ: 8.40 (d, J=0.8 Hz, 1H), 7.93(dd, J=2.0 Hz, 8.0 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz,1H), 6.86 (dd, J=2.4 Hz, 8.8 Hz, 1H), 6.79 (s, 1H), 3.94 (s, 3H),3.44-3.39 (m, 1H), 2.35-2.32 (m, 2H), 2.09-2.06 (m, 3H), 1.58-1.48 (m,2H), 2.28-1.18 (m, 2H). LCMS m/z 352.1 [M+H]⁺.

Step 2: methyl5-iodo-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoate

A mixture of methyl6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoate (1.0 g, 2.8mmol, 1.0 eq), TFA (97 mg, 0.8 mmol, 0.3 eq), NIS (0.95 g, 4.2 mmol, 1.5eq) in CH₃CN (20 mL) was stirred at rt for 4 h. The mixture wasconcentrated to give a residue which was purified by columnchromatography on silica (petroleum ether/EtOAc=5:1) to afford methyl5-iodo-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoate (679mg, yield 50%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ: 8.38 (d,J=1.6 Hz, 1H), 8.00 (dd, J=1.6 Hz, 8.4 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H),7.77 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 5.13 (br s, 1H),4.02-3.95 (m, 1H), 3.95 (s, 3H), 2.18-2.14 (m, 1H), 2.08-2.00 (m, 2H),1.89-1.82 (m, 2H), 1.77-1.67 (m, 4H). LCMS m/z 478.0 [M+H]⁺

Step 3: methyl5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoate

A mixture of methyl5-iodo-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoate (679mg, 1.4 mmol, 1.0 eq), FSO₂CF₂CO₂Me (2.7 g, 14.0 mmol, 10.0 eq), CuI(1.3 g, 7.0 mmol, 5.0 eq) and HMPA (2.5 g, 14.0 mmol, 10.0 eq) in DMF(10 mL) was stirred at 80° C. for 24 h under N₂. The mixture was dilutedwith EtOAc (150 mL) and washed with water (100 mL×2). The organic layerwas dried and concentrated to give a residue which was purified bycolumn chromatography on silica gel (petroleum ether/EtOAc=5:1) toafford methyl5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoateas a yellow solid (369 mg, yield 62%). ¹H NMR (400 MHz, CDCl₃) δ: 8.40(d, J=1.6 Hz, 1H), 8.04-7.97 (m, 2H), 7.87 (d, J=9.2 Hz, 1H), 7.09 (d,J=9.2 Hz, 1H), 5.52 (br s, 1H), 3.99 (s, 3H), 3.98 (s, 1H), 2.19-2.11(m, 1H), 2.04-2.01 (m, 2H), 1.88-1.84 (m, 2H), 1.77-1.59 (m, 4H). LCMSm/z 420.1 [M+H]⁺

Step 4:8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 105.¹H NMR (400 MHz, METHANOL-d₄) δ: 7.71-8.03 (m, 3H), 7.46 (dd, J=1.76,9.04 Hz, 1H), 7.21 (d, J=9.29 Hz, 1H), 4.65-4.72 (m, 1H), 4.16 (br. s.,1H), 3.95 (br. s., 1H), 2.79-2.97 (m, 1H), 2.11-2.30 (m, 1H), 1.62-2.08(m, 14H), 1.36-1.58 (m, 2H). LCMS m/z 543.2 [M+H]⁺

Example 191 9-(2-((trans-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

Step 1: methyl9-(2-((trans-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate

Into a mixture of2-((trans-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carboxylic acid(70 mg, 0.21 mmol, 1.0 eq), methyl9-aza-bicyclo[3.3.1]nonane-3-carboxylate HCl (56 mg, 0.25 mmol, 1.2 eq)and HATU (162 mg, 0.42 mmol, 2.0 eq) in DCM (20 mL) was added TEA (43mg, 0.42 mmol, 2.0 eq). The reaction was stirred at rt for 16 h. Themixture was washed with H₂O (2×20 mL) and concentrated. The residue waspurified by TLC on silica gel to give methyl9-(2-((trans-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate(80 mg, yield 80%) as a light yellow solid. LCMS m/z 493.3 [M+H]⁺

Step 2:9-(2-((trans-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

To a solution of methyl9-(2-((trans-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate(80 mg, 0.16 mmol, 1.0 eq) in THF/H₂O (5 mL, 4:1) was added NaOH (33 mg,0.81 mmol, 5.0 eq). The mixture was stirred at rt for 4 h. THF wasremoved and the residue was acidified to pH=6 with 1N HCl. The mixturewas directly purified by reversed phase HPLC (MeCN/water=5%˜95%) to give9-(2-((trans-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid as awhite solid (65 mg, yield 85%). ¹H NMR (400 MHz, CD₃OD) δ: 9.12 (s, 1H),7.88 (d, J=1.6 Hz, 1H), 7.76 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.61 (d, J=8.8Hz, 1H), 4.90-4.85 (m, 1H), 4.30-4.25 (m, 1H), 4.05-4.00 (m, 1H),3.38-3.30 (m, 1H), 2.15-1.88 (m, 10H), 1.77-1.60 (m, 5H), 1.42-1.10 (m,4H), 0.92 (s, 9H); LCMS m/z 479.2 [M+H]⁺

Example 1929-((3-((cis-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1: 3-((cis-4-methylcyclohexyl)amino)isoquinoline-7-carbaldehyde

A mixture of 3-chloroisoquinoline-7-carbaldehyde (1.0 g, 5.23 mmol, 1.0eq), cis-4-methylcyclohexanamine (1.2 g, 10.46 mmol, 2.0 eq), Pd₂(dba)₃(480 mg, 0.52 mmol, 0.1 eq), Xphos (430 mg, 1.04 mmol, 0.2 eq) andCs₂CO₃ (3.4 g, 10.46 mmol, 2.0 eq) in DMF (10 mL) was stirred at 90° C.for 6 h under N₂ atmosphere. The mixture was diluted with water (50 mL)and extracted with DCM (50 mL×2). The combined organic layers werewashed with water (100 mL×2), dried over Na₂SO₄, filtrate andconcentrated. The crude product was purified by column chromatography onsilica gel (DCM/methanol=20:1) to give3-((cis-4-methylcyclohexyl)amino)isoquinoline-7-carbaldehyde as a yellowsolid (715 mg, yield: 51%). ESI-MS m/z 352.1 [M+H]⁺.

Step 2:9-((3-((cis-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, CD₃OD) δ: 8.96 (s, 1H), 8.12 (s, 1H), 7.79-7.74 (m,2H), 7.09 (s, 1H), 4.68-4.62 (m, 2H), 3.88-3.86 (m, 1H), 3.67 (s, 2H),3.45-3.33 (m, 1H), 2.60-2.51 (m, 2H), 2.31-2.05 (m, 6H), 1.90-1.34 (m,9H), 1.03-1.01 (m, 2H), 1.00 (d, J=6.4 Hz, 3H); ESI-MS (M+H)⁺: 422.2.

Example 1938-((4-chloro-3-((cis-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

Step 1:4-chloro-3-((cis-4-methylcyclohexyl)amino)isoquinoline-7-carbaldehyde

To a mixture of3-((cis-4-methylcyclohexyl)amino)isoquinoline-7-carbaldehyde (400 mg,1.49 mmol, 1.0 eq) and NCS (238 mg, 1.79 mmol, 1.2 eq) in CH₃CN (10 mL)was added TFA (58 mg, 0.45 mmol, 0.3 eq). The mixture was stirred at rtfor 16 h and concentrated. The residue was purified by columnchromatography on silica gel (petroleum ether/EtOAc=20:1) to give4-chloro-3-((cis-4-methylcyclohexyl)amino)isoquinoline-7-carbaldehyde asa yellow solid (324 mg, yield 72%). ESI-MS (M+H)⁺: 303.3.

Step 2:8-((4-chloro-3-((cis-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, CD₃OD) δ: 8.91 (s, 1H), 8.05 (s, 1H), 7.99 (d, J=8.8Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 4.32 (s, 2H), 4.34-4.30 (m, 1H),4.06-4.03 (m, 2H), 3.01-2.96 (m, 1H), 2.54-2.51 (m, 2H), 2.17-2.03 (m,6H), 1.87-1.66 (m, 7H), 1.40-1.32 (m, 2H), 1.02 (d, J=6.0 Hz, 3H);ESI-MS (M+H)⁺: 442.2.

Example 1948-(3-((trans-4-(tert-butyl)cyclohexyl)amino)isoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

Step 1: methyl3-((trans-4-(tert-butyl)cyclohexyl)amino)isoquinoline-7-carboxylate

The preparation of the tile compound was the same as Example 193; step1: trans isomer was obtained as a yellow solid (350 mg, yield: 35%),along with cis isomer (300 mg, yield 33%). ESI-MS (M+H)⁺: 341.2.

Step 2:8-(3-((trans-4-(tert-butyl)cyclohexyl)amino)isoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 105.¹H NMR (400 MHz, CD₃OD) δ: 9.03 (s, 1H), 8.11 (s, 1H), 7.80 (d, J=9.2Hz, 1H), 7.75 (d, J=9.2 Hz, 1H), 7.25 (s, 1H), 4.82 (s, 1H), 4.27-4.24(m, 1H), 3.58-3.53 (m, 1H), 3.03-2.99 (m, 1H), 2.22-1.88 (m, 12H),1.43-1.25 (m, 4H), 1.17-1.11 (m, 1H), 0.93 (s, 9H); ESI-MS (M+H)⁺:464.3.

Example 195 9-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

Step 1: 7-((cis-4-ethylcyclohexyl)oxy)-3-methylisoquinoline

A mixture of 3-methylisoquinolin-7-ol (5.0 g, 31.4 mmol),(1r,4r)-4-ethylcyclohexyl methanesulfonate (7.1 g, 31.4 mmol) and Cs₂CO₃(10.3 g, 31.4 mmol) in t-BuOH (200 mL) was stirred at 90° C. for 6 h.The reaction was then cooled down. The mixture was filtered and thefiltrate was concentrated. The residue was purified by columnchromatography on silica gel (petroleum ether/EtOAc=20/1) to give thetitle compound as a white solid (5.7 g, yield: 40%). ESI-MS (M+H)⁺:270.2.

Step 2: 8-chloro-7-((cis-4-ethylcyclohexyl)oxy)-3-methylisoquinoline

To a solution of 7-((cis-4-ethylcyclohexyl)oxy)-3-methylisoquinoline(800 mg, 2.97 mmol) in acetonitrile (10 mL) was added NCS (475 mg, 3.57mmol), followed by TFA (101 mg, 0.89 mmol). The reaction was stirred atRT for 16 h. The mixture was then diluted with water (50 mL), andextracted with EtOAc (3×50 mL). The combined organic layers were driedand concentrated. The crude product was purified by columnchromatography on silica gel (petroleum ether/EtOAc=20/1) to give thetitle compound as a white solid (800 mg, yield: 89%). ESI-MS (M+H)⁺:304.1

Step 3:8-chloro-7-((cis-4-ethylcyclohexyl)oxy)isoquinoline-3-carbaldehyde

A mixture of8-chloro-7-((cis-4-ethylcyclohexyl)oxy)-3-methylisoquinoline (800 mg,2.64 mmol) and SeO₂ (586 mg, 5.28 mmol) in diphenyl oxide (5 mL) wasstirred at 180° C. for 6 h and cooled down. The mixture was filtered andthe filtrate was concentrated. The residue was purified by columnchromatography on silica gel (petroleum ether/EtOAc=100%-95%) to givethe title compound as a yellow solid (418 g, yield: 50%). ESI-MS (M+H)⁺:318.2.

Step 4: Isopropyl9-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methy)-9-azabicyclo[3.3.1]nonane-3-carboxylate

A mixture of8-chloro-7-((cis-4-ethylcyclohexyl)oxy)isoquinoline-3-carbaldehyde (100mg, 0.315 mmol), methyl 9-azabicyclo[3.3.1]nonane-3-carboxylatehydrochloride (83 mg, 0.378 mmol) and titanium(IV) isopropoxide (179 mg,0.63 mmol) in THF (3 mL) was stirred at 80° C. for 2 h in a sealed tube.The mixture was cooled to RT and NaBH(OAc)₃ (134 mg, 0.630 mmol) wasadded. The reaction was stirred at 80° C. for 1 h. Water (30 mL) wasadded and the mixture was extracted with CH₂Cl₂ (2×30 mL). The combinedorganic layer was washed with water (2×60 mL), separated, and then driedover Na₂SO₄, and concentrated. The residue was purified by columnchromatography on silica gel (petroleum ether/EtOAc=5:1) to give thetitle compound as colorless oil (93 mg, yield: 58%). ESI-MS (M+H)⁺:513.3.

Step 5:9-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

To a solution of isopropyl9-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate(100 mg, 0.195 mmol) in 10 mL of MeOH was added a solution of NaOH (23mg, 0.58 mmol) in H₂O (5 mL). The reaction mixture was stirred at 65° C.for 2 h. The solvent was removed and water (10 mL) was added. Themixture was acidified to pH=6 with 1N HCl. The solid was collected byfiltration and purified by HPLC (MeCN/H₂O-0.05% TFA) to give the titlecompound as a white solid (64 mg, yield: 70%). ¹H NMR (400 MHz, CD₃OD)δ: 9.62 (s, 1H), 8.00 (s, 1H), 7.95 (d, J=9.2 Hz, 1H), 7.79 (d, J=9.2Hz, 1H), 4.93 (s, 1H), 4.72 (s, 2H), 3.58-3.54 (m, 2H), 3.15-3.08 (m,1H), 2.46-2.31 (m, 4H), 2.19-2.04 (m, 5H), 1.93-1.90 (m, 2H), 1.81-1.49(m, 7H), 1.38-1.33 (m, 3H), 0.94 (t, J=6.8 Hz, 3H). ESI-MS (M+H)⁺:471.2.

Example 196 9-((8-bromo-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

Step 1: 8-bromo-7-((cis-4-ethylcyclohexyl)oxy)-3-methylisoquinoline

Bromine (1.2 g, 7.44 mmol, 2.0 eq) was added to a solution of7-((cis-4-ethylcyclohexyl)oxy)-3-methylisoquinoline (1.0 g, 3.72 mmol)in AcOH (20 mL) at rt. The mixture was stirred at RT for 3 h. After thereaction completed, the mixture was diluted with water (50 mL) andextracted with EtOAc (2×50 mL). The combined organic layer was washedwith water (2×100 mL), aq. NaHCO₃ (100 mL), dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (petroleum ether/EtOAc=20/1) to give the title compound as awhite solid (1.1 g, yield: 85%). ESI-MS (M+H)⁺: 348.1.

Step 1:8-bromo-7-((cis-4-ethylcyclohexyl)oxy)isoquinoline-3-carbaldehyde

The title compound was prepared according to the method of Example 196to give a yellow solid (400 mg, yield: 67%). ESI-MS (M+H)⁺: 362.2.

Step 2: Isopropyl9-((8-bromo-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate

The title compound was prepared according to the method of Example 196to give a yellow solid (109 mg, yield: 60%). ESI-MS (M+H)⁺: 557.2.

Step 3:9-((8-bromo-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 196to give a yellow solid (80 mg, yield: 70%). ¹H NMR (400 MHz, CD₃OD) δ:9.50 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.65 (d, J=8.8 Hz,1H), 4.85 (s, 1H), 4.65 (s, 2H), 3.50-3.48 (m, 2H), 3.09-3.00 (m, 1H),2.36-2.22 (m, 4H), 2.06-1.93 (m, 5H), 1.83-1.81 (m, 2H), 1.71-1.43 (m,7H), 1.26-1.18 (m, 3H), 0.84 (t, J=6.8 Hz, 3H). ESI-MS (M+H)⁺: 515.2.

Example 1979-((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

Step 1: 8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)isoquinoline-3-carbaldehyde

A mixture of8-iodo-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)isoquinoline-3-carbaldehyde(500 mg, 1.11 mmol), HMPA (1.99 g, 11.13 mmol), CuI (527 mg, 2.27 mmol)and FSO₂CF₂CO₂CH₃ (2.11 g, 11.13 mmol) in DMF (5 mL) was stirred in asealed tube at 90° C. for 16 h. The reaction mixture was concentratedand the residue was purified by column chromatography on silica gel(petroleum ether/EtOAc=20:1) to yield the title compound as a yellowsolid (130 mg, yield: 30%). ESI-MS (M+H)⁺: 392.1.

Step 2: Isopropyl9-((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate

The title compound was prepared according to the method of Example 196to give the title compound as a yellow solid (80 mg, yield: 60%). ESI-MS(M+H)⁺: 587.3.

Step 3:9-((8-(trifluoromethyl)-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 196to give the title compound as a yellow solid (58 mg, yield: 70%). ¹H NMR(400 MHz, CD₃OD) δ: 9.65 (s, 1H), 8.23 (d, J=9.6 Hz, 1H), 8.05 (s, 1H),7.88 (d, J=9.6 Hz, 1H), 5.09 (s, 1H), 4.80 (s, 2H), 3.76-3.72 (m, 2H),3.45-3.40 (m, 1H), 2.52-1.90 (m, 12H), 1.87-1.75 (m, 7H). ESI-MS (M+H)⁺:545.1.

Example 1989-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)amino)bicyclo[3.3.1]nonane-3-carboxylicacid

Step 1: 6-((cis-4-ethylcyclohexyl)oxy)quinoline

To a solution of quinolin-6-ol (9.5 g, 65.5 mmol) andcis-4-ethylcyclohexyl methanesulfonate (14.8 g, 72.0 mmol) in t-BuOH(150 mL) was added Cs₂CO₃ (21.3 g, 65.5 mmol). The mixture was stirredat 90° C. for 10 h. The mixture was cooled down, diluted with water (200mL) and extracted with EtOAc (300 mL×2). The combined organic layerswere dried over Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography on silica gel (petroleum ether/EtOAc=15/1) to givethe title compound as a white solid (12.0 g, yield: 72%). ESI-MS (M+H)⁺:256.2.

Step 2: 6-((cis-4-Ethylcyclohexyl)oxy)quinoline 1-oxide

To a solution of 6-((cis-4-ethylcyclohexyl)oxy)quinoline (2.0 g, 7.84mmol) in CH₂Cl₂ (30 mL) was portionwise added m-CPBA (2.7 g, 15.68mmol). The mixture was stirred at RT for 16 h. Aqueous Na₂SO₃ (50 mL)was added and the mixture was stirred at RT for 30 min. The mixture wasseparated and the aqueous was extracted with CH₂Cl₂ (50 mL). Thecombined organics were washed with water (100 mL), dried over Na₂SO₄,filtered and concentrated. The crude product was purified by columnchromatography on silica gel (DCM/methanol=20/1) to give the titlecompound as a yellow solid (1.8 g, yield: 83%). ESI-MS (M+H)⁺: 272.1.

Step 3: 2-Chloro-6-((cis-4-ethylcyclohexyl)oxy)quinoline

A mixture of 6-((cis-4-ethylcyclohexyl)oxy)quinoline 1-oxide (9.0 g, 33mmol) in POCl₃ (50 mL) was heated at 100° C. for 16 h and cooled down.The mixture was carefully poured onto ice water (200 mL). The aqueouswas neutralized with NaOH and extracted with DCM (100 mL×3). Thecombined organics were dried over Na₂SO₄, and concentrated. The residuewas purified by column chromatography on silica gel (petroleumether/EtOAc=100:1) to give the title compound as a yellow solid (6.0 g,yield: 63%). ESI-MS (M+H)⁺: 290.1. An isomer4-chloro-6-((cis-4-ethylcyclohexyl)oxy)quinoline was also isolated (2.9g, yield: 30%) as a yellow solid.

Step 4: 2-chloro-6-((cis-4-ethylcyclohexyl)oxy)-5-iodoquinoline

To a solution of 2-chloro-6-((cis-4-ethylcyclohexyl)oxy)quinoline (100mg, 0.35 mmol) in acetonitrile (2 mL) was added NIS (93 mg, 0.42 mmol),followed by TFA (8 mg, 0.07 mmol). The mixture was stirred at RT for 16h. The solvent was removed under vacuo. The residue was purified bycolumn chromatography on silica gel (petroleum ether/EtOAc=10/1) to givethe title compound as a yellow solid (130 mg, yield: 92%). ¹H NMR (400MHz, CDCl₃) δ: 8.38 (d, J=8.8 Hz, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.40-7.35(m, 2H), 4.82 (s, 1H), 2.07-2.06 (m, 2H), 1.69-1.58 (m, 6H), 1.36-1.28(m, 3H), 0.92 (t, J=7.2 Hz, 3H). ESI-MS (M+H)⁺: 416.1.

Step 5:2-chloro-6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)quinoline

The title compound was prepared according to the method of Example 198to give the title compound as a yellow solid (70 mg, yield: 63%). ESI-MS(M+H)⁺: 358.1.

Step 6: Methyl9-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)amino)bicyclo[3.3.1]nonane-3-carboxylate

A mixture of 2-chloro-6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)quinoline (70 mg, 0.2 mmol), methyl9-aminobicyclo[3.3.1]nonane-3-carboxylate (58 mg, 0.3 mmol), Cs₂CO₃ (130mg, 0.4 mmol), S-phos (16 mg, 0.04 mmol) and Pd₂(dba)₃ (18 mg, 0.02mmol) in DMF (2 mL) was stirred at 100° C. for 16 h under N₂ atmosphere.Water (20 mL) was added and the mixture was extracted with EtOAc (20mL×3). The organic phase was dried and concentrated. The residue waspurified by reversed phase HPLC (MeOH/H₂O-0.05% TFA) to give the titlecompound as a yellow solid (30 mg, yield 30%). ESI-MS (M+H)⁺: 519.2.

Step 7:9-((6-((cis-4-Ethylcyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)amino)bicyclo[3.3.1]nonane-3-carboxylicacid

To a solution of methyl9-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)amino)bicyclo[3.3.1]nonane-3-carboxylate (30 mg, 0.06mmol) in MeOH (1 mL) was added NaOH (7 mg, 0.17 mmol) and H₂O (0.5 mL).The reaction mixture was stirred at 65° C. for 16 h. Then the reactionwas cooled to RT, acidified with 1N HCl to pH =6. The mixture wasdirectly purified by reversed phase HPLC (MeOH/H₂O) to give the titlecompound as a white solid (15 mg, yield: 52%). ¹H NMR (400 MHz, CD₃OD, amixture of cis and trans isomers) δ: 8.05-8.02 (m, 1H), 7.69-7.65 (m,1H), 7.35-7.31 (m, 1H), 6.90-6.80 (m, 1H), 4.66 (s, 1H), 4.21-4.17 (m,0.5H), 3.70-3.69 (m, 0.5H), 2.88-2.74 (m, 1H), 2.29-1.91 (m, 6H),1.78-1.19 (m, 17H), 0.82 (t, J=6.8 Hz, 3H). ESI-MS (M+H)⁺: 505.2.

Example 1999-((5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 188.¹H NMR (400 MHz, CD₃OD) δ: 8.17 (d, J=9.6 Hz, 1H), 8.08 (s, 1H), 8.04(d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 5.00(s, 1H), 4.45 (s, 2H), 3.33-3.30 (m, 2H), 3.07-3.05 (m, 1H), 2.39-2.21(m, 4H), 2.09-2.07 (m, 3H), 1.95-1.91 (m, 2H), 1.74-1.52 (m, 9H),1.37-1.30 (m, 3H), 0.95 (t, J=6.8 Hz, 3H). LCMS m/z 461.2 [M+H]⁺

Example 2008-((5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 188.¹H NMR (400 MHz, CD₃OD) δ: 8.21 (d, J=9.6 Hz, 1H), 8.12 (s, 1H), 8.09(d, J=8.8 Hz, 1H), 7.82 (dd, J=1.6 Hz, 8.4 Hz, 1H), 7.57 (d, J=9.2 Hz,1H), 5.03 (s, 1H), 4.33 (s, 2H), 3.90-3.88 (m, 2H), 2.72-2.65 (m, 1H),2.44-2.41 (m, 2H), 2.09-1.95 (m, 8H), 1.72-1.33 (m, 6H), 1.37-1.33 (m,3H), 0.95 (t, J=6.8 Hz, 3H). LCMS m/z 447.2 [M+H]⁺

Example 2019-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 186.¹H NMR (400 MHz, CD₃OD) δ: 8.16 (d, J=8.4 Hz, 1H), 7.86-7.81 (m, 2H),7.52 (d, J=9.2 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 4.83 (s, 1H), 3.85-3.82(m, 1H), 3.20-3.12 (m, 1H), 2.20-1.77 (m, 14H), 1.67-1.58 (m, 6H). LCMSm/z 524.2 [M+H]⁺

Example 2028-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 92.¹H NMR (400 MHz, CD₃OD) δ: 8.33 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.90(d, J=8.8 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.54 (d, J=9.2 Hz, 1H), 4.95(s, 1H), 4.23-4.19 (m, 2H), 3.52-3.49 (m, 1H), 2.69-2.62 (m, 1H),2.39-1.68 (m, 19H), 0.77 (t, J=7.2 Hz, 3H). LCMS m/z 524.2 [M+H]⁺

Example 2038-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 186.¹H NMR (400 MHz, CD₃OD) δ: 8.17 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.83(d, J=8.8 Hz, 1H), 7.56 (dd, J=1.2 Hz, 8.8 Hz, 1H), 7.41 (d, J=8.8 Hz,1H), 4.78 (s, 1H), 4.14-4.09 (m, 1H), 2.92-2.88 (m, 1H), 2.04-1.74 (m,11H), 1.60-1.44 (m, 7H), 0.89 (d, J=6.0 Hz, 3H). LCMS m/z 456.1.1 [M+H]⁺

Example 2048-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 92.¹H NMR (400 MHz, CD₃OD) δ: 8.32 (d, J=8.8 Hz, 1H), 8.15 (d, J=9.6 Hz,1H), 8.06 (s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.61 (d, J=9.6 Hz, 1H), 5.02(s, 1H), 4.40-3.99 (m, 2H), 3.69-3.45 (m, 1H), 2.78-2.75 (m, 1H),2.46-2.39 (m, 2H), 2.32-1.91 (m, 11H), 1.74-1.67 (m, 6H), 1.56 (t,J=18.8 Hz, 3H), 0.78 (t, J=7.2 Hz, 3H). LCMS m/z 554.3 [M+H]⁺

Example 2058-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 93.¹H NMR (400 MHz, CD₃OD) δ: 8.32 (d, J=9.2 Hz, 1H), 8.02 (s, 1H), 7.88(d, J=8.8 Hz, 1H), 7.74 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.52 (d, J=9.2 Hz,1H), 4.87 (s, 1H), 4.46-4.42 (m, 1H), 4.34-4.30 (m, 1H), 3.53-3.49 (m,1H), 2.71-2.63 (m, 1H), 2.41-2.37 (m, 1H), 2.27-1.79 (m, 12H), 1.69-1.53(m, 7H), 0.97 (d, J=4.8 Hz, 3H). LCMS m/z 456.2 [M+H]⁺

Example 2069-(5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 187.¹H NMR (400 MHz, DMSO-d₆) δ: 8.38 (d, J=9.2 Hz, 1H), 8.11 (s, 1H), 7.98(d, J=8.4 Hz, 1H), 7.75-7.71 (m, 2H), 5.15 (s, 1H), 4.76-4.72 (m, 1H),3.85-3.81 (m, 1H), 3.20-3.15 (m, 1H), 2.46-2.42 (m, 1H), 2.09-1.96 (m,4H), 1.92-1.59 (m, 14H). LCMS m/z 515.2 [M+H]⁺

Example 2079-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 188.¹H NMR (400 MHz, CD₃OD) δ: 8.21 (d, J=9.2 Hz, 1H), 8.15 (s, 1H), 8.08(d, J=8.4 Hz, 1H), 7.85 (dd, J=1.6 Hz, 8.4 Hz, 1H), 7.57 (d, J=9.2 Hz,1H), 5.01 (s, 1H), 4.62 (s, 2H), 3.53-3.50 (m, 2H), 3.09-3.05 (m, 1H),2.44-2.38 (m, 4H), 2.14-2.04 (m, 5H), 1.84-1.71 (m, 5H), 1.59-1.56 (m,5H), 0.98 (d, J=7.6 Hz, 3H). LCMS m/z 447.2 [M+H]⁺

Example 2089-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 186.¹H NMR (400 MHz, DMSO-d₆) δ: 8.12 (d, J=8.8 Hz, 1H), 8.02 (d, J=9.2 Hz,1H), 7.96 (s, 1H), 7.69-7.57 (m, 2H), 4.92 (s, 1H), 4.68-4.63 (m, 1H),3.76-3.70 (m, 1H), 2.71-2.68 (m, 1H), 2.06-1.40 (m, 19H), 0.92 (d, J=6.0Hz, 3H). LCMS m/z 470.2 [M+H]⁺

Example 2099-((6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoro-methyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, CD₃OD) δ: 8.15 (d, J=8.4 Hz, 1H), 8.05-8.01 (m, 2H),7.64 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.47 (d, J=9.6 Hz, 1H), 4.90 (s, 1H),4.54 (s, 2H), 3.46-3.44 (m, 2H), 3.03-2.99 (m, 1H), 2.35-1.98 (m, 10H),1.90-1.56 (m, 9H), 1.45 (t, J=18.8 Hz, 3H); LCMS ml/z 540.2 [M+H]⁺

Example 2108-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 92.¹H NMR (400 MHz, CD₃OD) δ: 8.34 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.89(d, J=9.2 Hz, 1H), 7.71 (dd, J=1.2 Hz, 8.8 Hz, 1H), 7.53 (d, J=9.6 Hz,1H), 4.89-4.86 (m, 1H), 4.44-4.38 (m, 1H), 4.13-4.08 (m, 1H), 2.71-2.63(m, 1H), 2.44-2.36 (m, 2H), 2.44-1.81 (m, 11H), 1.70-1.54 (m, 7H),0.99-0.96 (m, 3H), 0.78 (t, J=7.2 Hz, 3H). LCMS m/z 470.2 [M+H]⁺

Example 2119-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 92.¹H NMR (400 MHz, CD₃OD) δ: 8.32 (d, J=8.8 Hz, 1H), 8.08 (s, 1H), 7.89(d, J=8.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 4.89(s, 1H), 4.84-4.79 (m, 1H), 3.23-3.30 (m, 2H), 3.06-3.00 (m, 1H),2.43-1.53 (m, 21H), 0.98 (d, J=5.2 Hz, 3H), 0.75 (t, J=7.2 Hz, 3H). LCMSm/z 484.3 [M+H]+

Example 2128-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 189.¹H NMR (400 MHz, CD₃OD) δ: 8.20 (d, J=8.8 Hz, 1H), 8.15-8.10 (m, 2H),7.85 (dd, J=2.0 Hz, 9.2 Hz, 1H), 7.59 (d, J=9.6 Hz, 1H), 5.03 (s, 1H),4.48-4.45 (m, 1H), 4.28-4.24 (m, 1H), 3.56-3.51 (m, 1H), 2.71-2.65 (m,1H), 2.44-2.38 (m, 1H), 2.27-2.20 (m, 2H), 2.10-1.49 (m, 16H), 1.37-1.33(m, 3H), 0.95 (t, J=7.6 Hz, 3H). LCMS m/z 461.3 [M+H]⁺

Example 2139-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 189.¹H NMR (400 MHz, CD₃OD) δ: 8.20 (d, J=9.2 Hz, 1H), 8.16 (s, 1H), 8.12(d, J=9.2 Hz, 1H), 7.89 (d, J=9.2 Hz, 1H), 7.57 (d, J=9.2 Hz, 1H),5.03-5.00 (m, 2H), 3.72-3.70 (m, 2H), 3.05-3.03 (m, 1H), 2.48-2.00 (m,8H), 1.77-1.51 (m, 12H), 1.37-1.30 (m, 4H), 0.95 (t, J=7.6 Hz, 3H). LCMSm/z 475.3 [M+H]⁺

Example 2149-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 93.¹H NMR (400 MHz, CD₃OD) δ: 8.21 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 7.79(d, J=9.2 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H),5.02-4.96 (m, 1H), 4.81-4.77 (m, 2H), 3.55-3.50 (m, 1H), 3.01-2.96 (m,1H), 2.43-2.35 (m, 1H), 2.24-1.92 (m, 8H), 1.74-1.44 (m, 13H), 0.88 (d,J=5.6 Hz, 3H). LCMS m/z 470.2 [M+H]⁺

Example 2158-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 186.¹H NMR (400 MHz, CD₃OD) δ: 8.24 (d, J=9.2 Hz, 1H), 8.00 (s, 1H), 7.91(d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.47 (d, J=9.2 Hz, 1H),4.86-4.82 (m, 2H), 4.21-4.15 (m, 1H), 3.02-2.93 (m, 1H), 2.16-1.82 (m,10H), 1.65-1.25 (m, 9H), 0.92 (t, J=7.2 Hz, 3H). LCMS m/z 470.2 [M+H]⁺

Example 2168-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 88.¹H NMR (400 MHz, CD₃OD) δ: 8.33 (d, J=9.2 Hz, 1H), 8.16 (d, J=9.2 Hz,1H), 8.05 (s, 1H), 7.75 (d, J=9.2 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 5.02(s, 1H), 4.57-4.55 (m, 1H), 4.47-4.38 (m, 1H), 3.48-3.46 (m, 1H),3.00-2.92 (m, 1H), 2.58-2.50 (m, 1H), 2.33-2.12 (m, 6H), 2.06-1.89 (m,4H), 1.84 (d, J=6.8 Hz, 3H), 1.76-1.67 (m, 6H), 1.56 (t, J=19.2 Hz, 3H).LCMS m/z 540.3 [M+H]⁺

Example 2179-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 88.¹H NMR (400 MHz, CD₃OD) δ: 8.33 (d, J=8.8 Hz, 1H), 8.16-8.13 (m, 2H),7.81 (d, J=9.2 Hz, 1H), 7.62 (d, J=9.6 Hz, 1H), 5.22-5.20 (m, 1H), 5.02(s, 1H), 4.22-4.20 (m, 1H), 3.40-3.32 (m, 1H), 3.19-3.16 (m, 1H),2.53-1.92 (m, 12H), 1.80-1.70 (m, 10H), 1.61 (t, J=18.8 Hz, 3H). LCMSm/z 554.3 [M+H]⁺

Example 2189-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 187.¹H NMR (400 MHz, DMSO-d₆) δ: 8.36 (d, J=9.2 Hz, 1H), 810 (s, 1H), 7.97(d, J=8.4 Hz, 1H), 7.72-7.69 (m, 2H), 5.07 (s, 1H), 4.75-4.72 (m, 1H),3.84-3.80 (m, 1H), 3.26-3.18 (m, 1H), 2.02-1.38 (m, 19H), 0.93 (d, J=6.4Hz, 3H). LCMS m/z 461.2 [M+H]⁺

Example 2198-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 187.¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=9.2 Hz, 1H), 8.10-8.08 (m, 2H),7.77 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 5.03-5.02 (m,1H), 4.86-4.83 (m, 1H), 4.22-4.18 (m, 1H), 3.01-2.98 (m, 1H), 2.12-1.71(m, 12H), 1.60-1.55 (m, 5H), 0.99 (d, J=4.4 Hz, 3H). LCMS m/z 447.2[M+H]⁺

Example 2208-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 189.¹H NMR (400 MHz, CD₃OD) δ: 8.12 (d, J=9.2 Hz, 1H), 7.98-7.93 (m, 2H),7.81 (d, J=8.0 Hz, 1H), 7.47 (d, J=9.6 Hz, 1H), 4.99 (s, 1H), 3.91-3.87(m, 1H), 3.38-3.34 (m, 1H), 3.20-3.15 (m, 1H), 2.60-2.55 (m, 1H),2.10-1.99 (m, 7H), 1.74-1.31 (m, 14H), 0.95 (t, J=7.2 Hz, 3H), 0.66 (t,J=7.2 Hz, 3H). LCMS m/z 475.2 [M+H]⁺

Example 2219-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 187.¹H NMR (400 MHz, CD₃OD) δ: 8.24 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.4 Hz,1H), 8.03 (d, J=1.2 Hz, 1H), 7.71 (dd, J=1.6 Hz, 8.4 Hz, 1H), 7.57 (d,J=9.2 Hz, 1H), 5.03 (s, 1H), 4.93-4.89 (m, 1H), 4.00-3.95 (m, 1H),3.42-3.35 (m, 1H), 2.12-1.92 (m, 10H), 1.72-1.52 (m, 8H), 1.37-1.33 (m,3H), 0.95 (t, J=6.8 Hz, 3H). LCMS m/z 475.2 [M+H]⁺

Example 2228-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 104.¹H NMR (400 MHz, DMSO-d₆) δ: 8.32 (d, J=9.6 Hz, 1H), 8.13-8.09 (m, 2H),7.68 (d, J=8.8 Hz, 2H), 5.04 (s, 1H), 4.71-4.68 (m, 1H), 4.14-4.10 (m,1H), 2.85-2.67 (m, 1H), 1.97-1.51 (m, 14H), 1.33-1.23 (m, 5H), 0.87 (t,J=7.2 Hz, 3H). LCMS m/z 504.2 [M+H]⁺

Example 2238-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 187.¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=9.6 Hz, 1H), 8.11-8.07 (m, 2H),7.78 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.58 (d, J=9.6 Hz, 1H), 5.03 (s, 1H),4.89-4.80 (m, 1H), 4.19-4.15 (m, 1H), 2.95-2.88 (m, 1H), 2.11-1.52 (m,16H), 1.37-1.29 (m, 3H), 0.95 (t, J=7.2 Hz, 3H). LCMS m/z 461.2 [M+H]⁺

Example 2249-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 104.¹H NMR (400 MHz, CD₃OD) δ: 8.09 (d, J=7.2 Hz, 1H), 8.00 (d, J=9.2 Hz,1H), 7.84 (s, 1H), 7.47 (dd, J=2.0 Hz, 9.2 Hz, 1H), 7.41 (d, J=9.2 Hz,1H), 4.80 (s, 1H), 3.82-3.78 (m, 1H), 3.13-3.06 (m, 1H), 2.06-1.73 (m,10H), 1.59-1.15 (m, 12H), 0.79 (t, J=7.2 Hz, 3H). LCMS m/z 518.2 [M+H]⁺

Example 2259-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 189.¹H NMR (400 MHz, CD₃OD) δ: 8.20 (d, J=9.6 Hz, 1H), 8.16 (s, 1H), 8.12(d, J=8.8 Hz, 1H), 7.89 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.57 (d, J=9.6 Hz,1H), 5.04-5.01 (m, 2H), 3.75-3.68 (m, 2H), 3.07-3.02 (m, 1H), 2.48-1.95(m, 9H), 1.56-1.72 (m, 8H), 1.58-1.54 (m, 5H), 0.99 (d, J=4.8 Hz, 3H).LCMS m/z 461.2 [M+H]³⁰

Example 2268-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 92.¹H NMR (400 MHz, CD₃OD) δ: 8.21 (d, J=9.2 Hz, 1H), 8.18 (d, J=8.8 Hz,1H), 8.17 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.61 (d, J=9.2 Hz, 1H), 5.03(s, 1H), 4.63-4.47 (m, 1H), 4.23-4.11 (m, 1H), 3.51-3.39 (m, 1H),2.99-2.91 (m, 1H), 2.53-2.40 (m, 2H), 2.31-1.90 (m, 10H), 1.77-1.68 (m,2H), 1.57-1.48 (m, 5H), 0.98 (d, J=5.6 Hz, 3H), 0.80 (t, J=7.6 Hz, 3H).LCMS m/z 461.2 [M+H]⁺

Example 2279-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 186.¹H NMR (400 MHz, CD₃OD) δ: 8.26 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 7.91(d, J=9.2 Hz, 1H), 7.62 (dd, J=1.2 Hz, 8.8 Hz, 1H), 7.50 (d, J=9.2 Hz,1H), 4.90-4386 (m, 2H), 3.95-3.92 (m, 1H), 3.29-3.19 (m, 1H), 2.20-1.85(m, 10H), 1.74-1.54 (m, 8H), 1.37-1.29 (m, 3H), 0.94 (t, J=7.2 Hz, 3H).LCMS m/z 484.2 [M+H]⁺

Example 2289-(1-(5-cyano-6-(((1s,4s)-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 189.¹H NMR (400 MHz, CD₃OD) δ: 8.25-8.17 (m, 3H), 7.91 (d, J=8.8 Hz, 1H),7.62 (d, J=9.2 Hz, 1H), 5.26-5.22 (m, 1H), 5.09 (s, 1H), 4.23-4.19 (m,1H), 3.43-3.36 (m, 1H), 3.18-3.14 (m, 1H), 2.56-2.15 (m, 10H), 2.07-1.65(m, 12H). LCMS m/z 515.2 [M+H]⁺

Example 2299-((5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 188.¹H NMR (300 MHz, METHANOL-d₄) δ 8.03-8.30 (m, 3H), 7.86 (dd, J=1.89,8.69 Hz, 1H), 7.61 (d, J=9.06 Hz, 1H), 5.08 (br. s, 1H), 4.67-4.78 (m,2H), 3.65 (br. s., 2H), 3.37-3.51 (m, 1H), 1.64-2.75 (m, 19H). LCMS m/z501.1 [M+H]⁺

Example 2309-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 108.¹H NMR (400 MHz, METHANOL-d₄) δ 7.70-8.01 (m, 3H), 7.53 (d, J=9.04 Hz,1H), 7.23 (d, J=9.54 Hz, 1H), 4.42-4.64 (m, 2H), 3.95 (br. s, 1H),3.48-3.64 (m, 2H), 3.26-3.36 (m, 1H), 2.36-2.61 (m, 2H), 1.86-2.31 (m,9H), 1.56-1.85 (m, 6H), 1.38-1.55 (m, 2H). LCMS m/z 543.3 [M+H]⁺

Example 231 methyl8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylate

The title compound was prepared according to the method of Example 190.¹H NMR (400 MHz, METHANOL-d₄) δ 7.87-8.11 (m, 3H), 7.58 (d, J=9.04 Hz,1H), 7.33 (d, J=9.29 Hz, 1H), 4.65-4.75 (m, 1H), 4.28 (br. s., 1H), 4.07(br. s., 1H), 3.70 (s, 3H), 2.94-3.12 (m, 1H), 2.28-2.39 (m, 1H),1.73-2.20 (m, 14H), 1.49-1.71 (m, 2H). LCMS m/z 557.0 [M+H]⁺

Example 2328-((r)-1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid andExample 2338-((s)-1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

8-(1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid (350 mg) was put under the following SFC separation yielded 141 mgof peak-1(chemical purity >99%, ee >99%) and 141 mg of peak-2(chemicalpurity >99%, ee >99%). IC (2×15 cm); 30% methanol (0.1% NPA)/CO₂, 100bar; 70 mL/min, 220 nm; inj vol.: 0.5 mL, 18 mg/mL methanol Peak-1 wasassigned as Example 233: ¹H NMR (400 MHz, METHANOL-d₄) δ 8.32 (d, J=8.53Hz, 1H), 8.12 (d, J=9.29 Hz, 1H), 8.01 (s, 1H), 7.68 (d, J=1.25 Hz, 1H),7.59 (d, J=9.29 Hz, 1H), 4.94 (br. s., 1H), 4.51-4.65 (m, 1H), 4.08 (dd,J=3.01, 11.55 Hz, 1H), 3.37-3.45 (m, 1H), 2.85-3.05 (m, 1H), 1.87-2.68(m, 12H), 1.70 (t, J=13.18 Hz, 2H), 1.33-1.58 (m, 5H), 0.96 (d, J=5.52Hz, 3H), 0.78 (t, J=7.28 Hz, 3H). LCMS m/z 504.1 [M+H]⁺

Peak-2 was assigned as Example 234: ¹H NMR (400 MHz, METHANOL-d₄) δ 8.32(d, J=8.53 Hz, 1H), 8.12 (d, J=9.29 Hz, 1H), 8.01 (s, 1H), 7.68 (d,J=1.25 Hz, 1H), 7.59 (d, J=9.29 Hz, 1H), 4.94 (br. s., 1H), 4.51-4.65(m, 1H), 4.08 (dd, J=3.01, 11.55 Hz, 1H), 3.37-3.45 (m, 1H), 2.85-3.05(m, 1H), 1.87-2.68 (m, 12H), 1.70 (t, J=13.18 Hz, 2H), 1.33-1.58 (m,5H), 0.96 (d, J=5.52 Hz, 3H), 0.78 (t, J=7.28 Hz, 3H). LCMS m/z 504.1[M+H]⁺

Example 234 8-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 88.¹H NMR (400 MHz, METHANOL-d₄) d 8.34 (d, J=8.78 Hz, 1H), 8.02 (s, 1H),7.91 (d, J=9.04 Hz, 1H), 7.74 (d, J=8.78 Hz, 1H), 7.55 (d, J=9.29 Hz,1H), 4.94 (br. s., 1H), 4.55 (br. s., 1H), 4.40 (d, J=6.53 Hz, 1H),3.40-3.52 (m, 1H), 2.85-3.04 (m, 1H), 2.48-2.53 (m, 1H), 2.08-2.36 (m,7H), 1.65-2.05 (m, 12H). LCMS m/z 510.0 [M+H]⁺

Example 2359-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 88.¹H NMR (400 MHz, METHANOL-d₄) d 8.34 (d, J=8.78 Hz, 1H), 8.10 (d, J=8.03Hz, 1H), 7.85-7.97 (m, 1H), 7.74-7.83 (m, 1H), 7.55 (d, J=9.29 Hz, 1H),5.02-5.29 (m, 1H), 4.94 (br. s, 1H), 4.09-4.31 (m, 1H), 3.33-3.45 (m,1H), 3.03-3.20 (m, 1H), 1.57-2.65 (m, 22H). LCMS m/z 524.0 [M+H]+

Example 2368-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 92.¹H NMR (400 MHz, METHANOL-d₄) δ 8.35 (d, J=8.78 Hz, 1H), 7.98 (s, 1H),7.88 (d, J=9.04 Hz, 1H), 7.67 (dd, J=1.38, 8.91 Hz, 1H), 7.54 (d, J=9.04Hz, 1H), 4.88 (br. s., 1H), 4.57 (d, J=6.53 Hz, 1H), 4.09 (dd, J=3.26,11.55 Hz, 1H), 3.35-3.44 (m, 1H), 2.83-3.03 (m, 1H), 1.85-2.66 (m, 12H),1.43-1.78 (m, 6H), 1.13-1.40 (m, 3H), 0.93 (t, J=7.15 Hz, 3H), 0.78 (t,J=7.28 Hz, 3H). LCMS m/z 484.1 [M+H]⁺

Example 2379-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 92.¹H NMR (400 MHz, METHANOL-d₄) δ 8.35 (d, J=7.78 Hz, 1H), 8.07 (br. s.,1H), 7.84-7.95 (m, 1H), 7.74 (br. s., 1H), 7.53 (d, J=9.04 Hz, 1H),4.83-4.93 (m, 1H), 4.70-4.80 (m, 1H), 4.21-4.30 (m, 1H), 3.37-3.45 (m,1H), 3.01-3.18 (m, 1H), 1.80-2.64 (m, 13H), 1.41-1.79 (m, 7H), 1.21-1.41(m, 3H), 0.93 (t, J=7.15 Hz, 3H), 0.75 (t, J=7.28 Hz, 3H). LCMS m/z498.0 [M+H]⁺

Example 2389-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid and Example 2399-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

9-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid (217 mg) was put under the following SFC separation yielded 42 mgof peak-1(chemical purity >99%, ee >99%) and 46 mg of peak-2(chemicalpurity >99%, ee >99%). Whelk0-1 from Regis Technologies (3×25 cm);acetonitrile:methanol (3:1) (1% isopropylamine)/CO₂, 100 bar; 80 mL/min,220 nm; inj vol.: 0.5 mL, 18 mg/mL methanol

Peak-1 was assigned as Example 239: ¹H NMR (400 MHz, METHANOL-d4) δ 8.33(d, J=9.04 Hz, 1H), 8.08 (d, J=8.03 Hz, 1H), 7.83-7.93 (m, 1H), 7.78 (d,J=8.78 Hz, 1H), 7.53 (d, J=9.04 Hz, 1H), 5.00-5.29 (m, 1H), 4.88 (br.s., 1H), 4.11-4.28 (m, 1H), 3.28-3.42 (m, 1H), 3.07-3.20 (m, 1H),1.40-2.65 (m, 21H), 1.21-1.41 (m, 3H), 0.93 (t, J=7.15 Hz, 3H). LCMS m/z484.1 [M+H]⁺

Peak-2 was assigned as Example 240: ¹H NMR (400 MHz, METHANOL-d4) δ 8.33(d, J=9.04 Hz, 1H), 8.08 (d, J=8.03 Hz, 1H), 7.83-7.93 (m, 1H), 7.78 (d,J=8.78 Hz, 1H), 7.53 (d, J=9.04 Hz, 1H), 5.00-5.29 (m, 1H), 4.88 (br.s., 1H), 4.11-4.28 (m, 1H), 3.28-3.42 (m, 1H), 3.07-3.20 (m, 1H),1.40-2.65 (m, 21H), 1.21-1.41 (m, 3H), 0.93 (t, J=7.15 Hz, 3H). LCMS m/z484.1 [M+H]⁺

Example 2409-((R)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid and Example 2419-((S)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

9-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid (285 mg) was put under the following SFC separation yielded 115 mgof peak-1(chemical purity >99%, ee >99%) and 122 mg of peak-2(chemicalpurity >99%, ee >99%). Whelk0-1 from Regis Technologies (3×25 cm);isopropanol:methanol (1:1) (1% isopropylamine)/CO₂, 100 bar; 80 mL/min,220 nm; inj vol.: 0.5 mL, 18 mg/mL methanol:dichloromethane (8:2)

Peak-1 was assigned as Example 241: ¹H NMR (400 MHz, METHANOL-d4) δ 8.34(d, J=8.78 Hz, 1H), 8.10 (d, J=8.03 Hz, 1H), 7.85-7.97 (m, 1H),7.74-7.83 (m, 1H), 7.55 (d, J=9.29 Hz, 1H), 5.02-5.29 (m, 1H), 4.94 (br.s., 1H), 4.09-4.31 (m, 1H), 3.33-3.45 (m, 1H), 3.03-3.20 (m, 1H),1.57-2.65 (m, 22H). LCMS m/z 524.0 [M+H]⁺

Peak-2 was assigned as Example 242: ¹H NMR (400 MHz, METHANOL-d4) δ 8.34(d, J=8.78 Hz, 1H), 8.10 (d, J=8.03 Hz, 1H), 7.85-7.97 (m, 1H),7.74-7.83 (m, 1H), 7.55 (d, J=9.29 Hz, 1H), 5.02-5.29 (m, 1H), 4.94 (br.s., 1H), 4.09-4.31 (m, 1H), 3.33-3.45 (m, 1H), 3.03-3.20 (m, 1H),1.57-2.65 (m, 22H). LCMS m/z 524.0 [M+H]⁺

Example 2428-((R)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid and Example 2438-((S)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

8-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid (300 mg) was put under the following SFC separation yielded 118 mgof peak-1(chemical purity >99%, ee >99%) and 118 mg of peak-2(chemicalpurity >99%, ee >99%). IC (2.1×25 cm); methanol (1% isopropylamine)/CO₂,100 bar; 80 mL/min, 220 nm; inj vol.: 0.5 mL, 18 mg/mL methanol

Peak-1 was assigned as Example 243: ¹H NMR (400 MHz, METHANOL-d₄) δ 8.34(d, J=8.78 Hz, 1H), 8.02 (s, 1H), 7.91 (d, J=9.04 Hz, 1H), 7.74 (d,J=8.78 Hz, 1H), 7.55 (d, J=9.29 Hz, 1H), 4.94 (br. s., 1H), 4.55 (br.s., 1H), 4.40 (d, J=6.53 Hz, 1H), 3.40-3.52 (m, 1H), 2.85-3.04 (m, 1H),2.48-2.53 (m, 1H), 2.08-2.36 (m, 7H), 1.65-2.05 (m, 12H) LCMS m/z 510.0[M+H]⁺

Peak-2 was assigned as Example 244: ¹H NMR (400 MHz, METHANOL-d₄) δ 8.34(d, J=8.78 Hz, 1H), 8.02 (s, 1H), 7.91 (d, J=9.04 Hz, 1H), 7.74 (d,J=8.78 Hz, 1H), 7.55 (d, J=9.29 Hz, 1H), 4.94 (br. s., 1H), 4.55 (br.s., 1H), 4.40 (d, J=6.53 Hz, 1H), 3.40-3.52 (m, 1H), 2.85-3.04 (m, 1H),2.48-2.53 (m, 1H), 2.08-2.36 (m, 7H), 1.65-2.05 (m, 12H) LCMS m/z 510.0[M+H]⁺

Example 244 methyl9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate

The title compound was prepared according to the method of Example 190.¹H NMR (400 MHz, METHANOL-d₄) δ 7.88-8.04 (m, 2H), 7.83 (d, J=1.76 Hz,1H), 7.49 (dd, J=1.76, 9.04 Hz, 1H), 7.30 (d, J=9.29 Hz, 1H), 4.88 (s,1H), 4.04 (br. s, 2H), 3.68 (s, 3H), 3.36-3.51 (m, 1H), 2.20-2.41 (m,1H), 1.42-2.17 (m, 18H). LCMS m/z 571.0 [M+H]⁺

Example 2459-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 190.¹H NMR 1H NMR (400 MHz, METHANOL-d₄) δ 7.90-8.06 (m, 2H), 7.83 (s, 1H),7.50 (dd, J=1.51, 9.04 Hz, 1H), 7.30 (d, J=9.29 Hz, 1H), 4.91 (s, 1H),4.04 (br. s, 2H), 3.36-3.45 (m, 1H), 2.22-2.45 (m, 1H), 1.45-2.17 (m,18H). LCMS m/z 557.0 [M+H]⁺

Example 2468-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid and Example 2478-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

8-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid (312 mg) was put under the following SFC separation yielded 118 mgof peak-1(chemical purity >99%, ee >99%) and 120 mg of peak-2(chemicalpurity >99%, ee >98%). IC (2×25 cm); 50% methanol (0.1% DEA)/CO₂, 100bar; 70 mL/min, 220 nm; inj vol.: 0.8 mL, 15.6 mg/mL methanol

Peak-1 was assigned as Example 247: 1H NMR (400 MHz, METHANOL-d₄) δ 8.35(d, J=8.78 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J=9.04 Hz, 1H), 7.67 (dd,J=1.38, 8.91 Hz, 1H), 7.54 (d, J=9.04 Hz, 1H), 4.88 (br. s., 1H), 4.57(d, J=6.53 Hz, 1H), 4.09 (dd, J=3.26, 11.55 Hz, 1H), 3.35-3.44 (m, 1H),2.83-3.03 (m, 1H), 1.85-2.66 (m, 12H), 1.43-1.78 (m, 6H), 1.13-1.40 (m,3H), 0.93 (t, J=7.15 Hz, 3H), 0.78 (t, J=7.28 Hz, 3H). LCMS m/z 484.1[M+H]⁺

Peak-2 was assigned as Example 248: ¹H NMR (400 MHz, METHANOL-d₄) δ 8.35(d, J=8.78 Hz, 1H), 7.98 (s, 1H), 7.88 (d, J=9.04 Hz, 1H), 7.67 (dd,J=1.38, 8.91 Hz, 1H), 7.54 (d, J=9.04 Hz, 1H), 4.88 (br. s., 1H), 4.57(d, J=6.53 Hz, 1H), 4.09 (dd, J=3.26, 11.55 Hz, 1H), 3.35-3.44 (m, 1H),2.83-3.03 (m, 1H), 1.85-2.66 (m, 12H), 1.43-1.78 (m, 6H), 1.13-1.40 (m,3H), 0.93 (t, J=7.15 Hz, 3H), 0.78 (t, J=7.28 Hz, 3H). LCMS m/z 484.1[M+H]⁺

Example 2489-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid and Example 2499-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

9-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid (99 mg) was put under the following SFC separation yielded 37 mg ofpeak-1(chemical purity >99%, ee >99%) and 39 mg of peak-2(chemicalpurity >99%, ee >98%). AS-H (2×25 cm); 30% ethanol (0.1% DEA)/CO₂, 100bar; 70 mL/min, 220 nm; inj vol.: 0.5 mL, 9.9 mg/mL methanol

Peak-1 was assigned as Example 249: 1H NMR (400 MHz, METHANOL-d₄) δ 8.35(d, J=7.78 Hz, 1H), 8.07 (br. s., 1H), 7.84-7.95 (m, 1H), 7.74 (br. s.,1H), 7.53 (d, J=9.04 Hz, 1H), 4.83-4.93 (m, 1H), 4.70-4.80 (m, 1H),4.21-4.30 (m, 1H), 3.37-3.45 (m, 1H), 3.01-3.18 (m, 1H), 1.80-2.64 (m,13H), 1.41-1.79 (m, 7H), 1.21-1.41 (m, 3H), 0.93 (t, J=7.15 Hz, 3H),0.75 (t, J=7.28 Hz, 3H). LCMS m/z 498.1[M+H]⁺

Peak-2 was assigned as Example 250: ¹H NMR (400 MHz, METHANOL-d₄) δ 8.35(d, J=7.78 Hz, 1H), 8.07 (br. s., 1H), 7.84-7.95 (m, 1H), 7.74 (br. s.,1H), 7.53 (d, J=9.04 Hz, 1H), 4.83-4.93 (m, 1H), 4.70-4.80 (m, 1H),4.21-4.30 (m, 1H), 3.37-3.45 (m, 1H), 3.01-3.18 (m, 1H), 1.80-2.64 (m,13H), 1.41-1.79 (m, 7H), 1.21-1.41 (m, 3H), 0.93 (t, J=7.15 Hz, 3H),0.75 (t, J=7.28 Hz, 3H). LCMS m/z 498.1[M+H]⁺

Example 2508-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid and Example 2518-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

8-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid (268 mg) was put under the following SFC separation yielded 89 mgof peak-1(chemical purity >99%, ee >99%) and 92 mg of peak-2(chemicalpurity >99%, ee >98%). AY-H (2×25 cm); 25% isopropanol (0.1% DEA)/CO₂,100 bar; 85 mL/min, 220 nm; inj vol.: 0.75 mL, 3 mg/mL methanol

Peak-1 was assigned as Example 251: ¹H NMR (400 MHz, METHANOL-d₄) δ 8.33(d, J=9.04 Hz, 1H), 7.99 (s, 1H), 7.88 (d, J=9.04 Hz, 1H), 7.71 (dd,J=1.51, 9.04 Hz, 1H), 7.53 (d, J=9.04 Hz, 1H), 4.88 (br. s., 1H), 4.54(d, J=6.27 Hz, 1H), 4.40 (q, J=6.53 Hz, 1H), 3.38-3.53 (m, 1H), 2.95(tt, J=5.93, 11.76 Hz, 1H), 2.46-2.63 (m, 1H), 1.75-2.37 (m, 12H),1.45-1.73 (m, 6H), 1.23-1.39 (m, 3H), 0.93 (t, J=7.15 Hz, 3H). LCMS m/z470.1 [M+H]⁺

Peak-2 was assigned as Example 252: ¹H NMR (400 MHz, METHANOL-d₄) δ 8.33(d, J=9.04 Hz, 1H), 7.99 (s, 1H), 7.88 (d, J=9.04 Hz, 1H), 7.71 (dd,J=1.51, 9.04 Hz, 1H), 7.53 (d, J=9.04 Hz, 1H), 4.88 (br. s., 1H), 4.54(d, J=6.27 Hz, 1H), 4.40 (q, J=6.53 Hz, 1H), 3.38-3.53 (m, 1H), 2.95(tt, J=5.93, 11.76 Hz, 1H), 2.46-2.63 (m, 1H), 1.75-2.37 (m, 12H),1.45-1.73 (m, 6H), 1.23-1.39 (m, 3H), 0.93 (t, J=7.15 Hz, 3H). LCMS m/z470.1 [M+H]⁺

Example 252 methyl8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylate

The title compound was prepared according to the method of Example 190.¹H NMR (400 MHz, METHANOL-d₄) d 8.05 (d, J=8.78 Hz, 1H), 7.90 (d, J=1.25Hz, 1H), 7.82 (d, J=9.04 Hz, 1H), 7.58 (dd, J=1.63, 8.66 Hz, 1H), 7.27(d, J=9.04 Hz, 1H), 4.81 (br. s., 1H), 4.24 (br. s., 1H), 3.99 (t,J=3.26 Hz, 1H), 3.67 (s, 3H), 3.03 (tt, J=5.87, 11.70 Hz, 1H), 2.21-2.38(m, 1H), 1.59-2.16 (m, 16H). LCMS m/z 523.0 [M+H]⁺

Example 2538-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 190.¹H NMR (400 MHz, METHANOL-d₄) d 8.06 (d, J=8.78 Hz, 1H), 7.91 (d, J=1.00Hz, 1H), 7.82 (d, J=9.04 Hz, 1H), 7.58 (dd, J=1.76, 8.78 Hz, 1H), 7.28(d, J=9.04 Hz, 1H), 4.81 (br. s., 1H), 4.25 (br. s., 1H), 4.00 (t,J=3.26 Hz, 1H), 2.98 (tt, J=5.99, 11.58 Hz, 1H), 2.22-2.43 (m, 1H),1.54-2.18 (m, 16H). LCMS m/z 509.0 [M+H]⁺

Example 254 9-(2-((cis-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

The title compound was prepared according to the method of Example 192.¹H NMR (400 MHz, CD₃OD) δ: 9.08 (s, 1H), 7.86 (d, J=1.2 Hz, 1H), 7.75(dd, J=2.0 Hz, 8.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 4.63-4.57 (m, 1H),4.05-4.00 (m, 1H), 3.90-3.85 (m, 1H), 3.37-3.33 (m, 1H), 2.18-1.73 (m,14H), 1.38-1.07 (m, 5H), 0.92 (s, 9H); LCMS m/z 479.3 [M+H]⁺

Example 255 8-((3-((trans-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 193.¹H NMR (400 MHz, CD₃OD) δ: 8.77 (s, 1H), 7.84 (s, 1H), 7.59 (s, 2H),6.65 (s, 1H), 3.98 (s, 2H), 3.62-3.58 (m, 2H), 3.53-3.50 (m, 1H),2.62-2.59 (m, 1H), 2.28-2.25 (m, 2H), 2.13-2.11 (m, 2H), 2.15-1.98 (m,2H), 1.90-1.88 (m, 2H), 1.82-1.78 (m, 4H), 1.45-1.43 (m, 1H), 1.31-1.24(m, 2H), 1.21-1.14 (m, 2H), 0.97 (d, J=6.4 Hz, 3H); ESI-MS (M+H)⁺:408.1.

Example 256 8-(2-((cis-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 192.¹H NMR (400 MHz, DMSO-d₆) δ: 9.30 (s, 1H), 8.04 (s, 1H), 7.82 (d, J=8.8Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 4.68-4.63 (m, 1H), 4.26-4.16 (m, 2H),2.89-2.85 (m, 1H), 1.96-1.75 (m, 10H), 1.59-1.36 (m, 6H), 1.06-1.00 (m,1H), 0.86 (s, 9H). LCMS m/z 465.3 [M+H]⁺

Example 257 8-(2-((trans-4-methylcyclohexyl)amino)quinazoline-6-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 192.¹H NMR (400 MHz, DMSO-d₆) δ: 9.27 (s, 1H), 8.20 (br s, 1H), 8.03 (s,1H), 7.82 (d, J=8.8 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 4.68-4.63 (m, 1H),4.18-4.10 (m, 2H), 2.88-2.84 (m, 1H), 1.94-1.71 (m, 12H), 1.40-1.31 (m,3H), 1.10-1.04 (m, 2H), 0.90 (d, J=6.4 Hz, 3H). LCMS m/z 423.2 [M+H]³⁰

Example 2589-((3-((trans-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 193.¹H NMR (400 MHz, CD₃OD) δ: 8.93 (s, 1H), 8.13 (s, 1H), 7.77 (s, 2H),7.10 (s, 1H), 4.65 (s, 2H), 3.69-3.66 (m, 2H), 3.59-3.53 (m, 1H),3.43-3.40 (m, 1H), 2.52-1.82 (m, 14H), 1.48-1.35 (m, 3H), 1.28-1.14 (m,2H), 0.98 (d, J=6.4 Hz, 3H). ESI-MS (M+H)⁺: 422.1.

Example 2598-((4-chloro-3-((trans-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 194.¹H NMR (400 MHz, CD₃OD) δ: 8.88 (s, 1H), 8.03 (s, 1H), 7.97 (d, J=8.8Hz, 1H), 7.74 (dd, J=1.6 Hz, 9.2 Hz, 1H), 4.31 (s, 2H), 4.07-4.01 (m,3H), 3.00-2.95 (m, 1H), 2.53-2.51 (m, 2H), 2.17-2.03 (m, 8H), 1.82-1.79(m, 2H), 1.48-1.35 (m, 3H), 1.20-1.11 (m, 2H), 0.97 (d, J=6.4 Hz, 3H);ESI-MS (M+H)⁺: 442.2.

Example 260 9-(3-(((1s,4s)-4-methylcyclohexyl)amino)isoquinoline-7-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

The title compound was prepared according to the method of Example 195.¹H NMR (400 MHz, CD₃OD) δ: 8.78 (s, 1H), 7.81 (s, 1H), 7.55 (d, J=8.4Hz, 1H), 7.43 (dd, J=1.6 Hz, 8.4 Hz, 1H), 6.60 (s, 1H), 4.79 (s, 1H),4.00-3.97 (m, 1H), 3.77-3.75 (m, 1H), 3.31-3.27 (m, 1H), 2.08-1.74 (m,10H), 1.68-1.61 (m, 4H), 1.56-1.53 (m, 3H), 1.34-1.25 (m, 2H), 0.92 (d,J=6.8 Hz, 3H); ESI-MS (M+H)⁺: 436.2.

Example 261 8-(3-((cis-4-methylcyclohexyl)amino)isoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 195.¹H NMR (400 MHz, CD₃OD) δ: 8.88 (s, 1H), 7.97 (s, 1H), 7.63 (d, J=8.4Hz, 1H), 7.56 (dd, J=1.6 Hz, 8.8 Hz, 1H), 6.68 (s, 1H), 4.81 (s, 1H),4.30-4.26 (m, 1H), 3.85-3.83 (m, 1H), 3.00-2.97 (m, 1H), 2.11-1.85 (m,10H), 1.77-1.69 (m, 2H), 1.65-1.61 (m, 3H), 1.42-1.34 (m, 2H), 1.00 (d,J=6.0 Hz, 3H); ESI-MS (M+H)⁺: 422.2.

Example 262 8-(2-((trans-4-(tert-butyl)cyclohexyl)amino)quinazoline-6-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 192.¹H NMR (400 MHz, DMSO-d₆) δ: 9.25 (s, 1H), 8.02 (s, 1H), 7.81 (d, J=8.0Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 4.68-4.63 (m, 1H), 4.15-4.10 (m, 1H),3.84-3.78 (m, 1H), 2.88-2.83 (m, 1H), 2.02-1.95 (m, 4H), 1.81-1.75 (m,8H), 1.32-1.29 (m, 2H), 1.14-1.00 (m, 3H), 0.87 (s, 9H). LCMS m/z 465.3[M+H]⁺

Example 2639-(3-((trans-4-methylcyclohexyl)amino)isoquinoline-7-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 195.¹H NMR (400 MHz, CD₃OD) δ: 8.84 (s, 1H), 7.88 (s, 1H), 7.62 (d, J=8.8Hz, 1H), 7.50 (dd, J=1.2 Hz, 8.8 Hz, 1H), 6.66 (s, 1H), 4.87 (s, 1H),4.09-4.05 (m, 1H), 3.56-3.50 (m, 1H), 3.39-3.34 (m, 1H), 2.14-2.08 (m,5H), 2.04-1.91 (m, 5H), 1.88-1.72 (m, 4H), 1.49-1.40 (m, 1H), 1.36-1.26(m, 2H), 1.21-1.11 (m, 2H), 0.97 (d, J=6.4 Hz, 3H); ESI-MS (M+H)⁺:436.2.

Example 264 8-(3-((trans-4-methylcyclohexyl)amino)isoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 195.¹H NMR (400 MHz, CD₃OD) δ: 8.86 (s, 1H), 7.96 (s, 1H), 7.62 (d, J=8.4Hz, 1H), 7.56 (dd, J=1.6 Hz, 8.8 Hz, 1H), 6.65 (s, 1H), 4.81 (s, 1H),4.30-4.28 (m, 1H), 3.57-3.54 (m, 1H), 3.01-2.97 (m, 1H), 2.14-1.79 (m,12H), 1.48-1.44 (m, 1H), 1.35-1.22 (m, 2H), 1.18-1.12 (m, 2H), 0.97 (d,J=6.4 Hz, 3H); ESI-MS (M+H)⁺: 422.2.

Example 265 9-(2-((trans-4-methylcyclohexyl)amino)quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

The title compound was prepared according to the method of Example 192.¹H NMR (400 MHz, DMSO-d₆) δ: 9.16 (br s, 1H), 7.85 (d, J=1.2 Hz, 1H),7.66 (d, J=8.8 Hz, 1H), 7.54-7.47 (m, 2H), 4.69 (s, 1H), 3.92-3.90 (m,1H), 3.85-3.76 (m, 1H), 3.24-3.22 (m, 1H), 1.99-1.61 (m, 14H), 1.36-1.29(m, 3H), 1.07-1.03 (m, 2H), 0.90 (d, J=6.4 Hz, 3H). ESI-MS (M+H)⁺:437.3.

Example 266 9-(2-((cis-4-methylcyclohexyl)amino)quinazoline-6-carbonyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

The title compound was prepared according to the method of Example 192.¹H NMR (400 MHz, DMSO-d₆) δ: 9.18 (s, 1H), 7.85 (s, 1H), 7.63 (d, J=8.4Hz, 1H), 7.47-7.43 (m, 2H), 4.70-4.65 (m, 1H), 4.08-4.02 (m, 1H),3.93-3.87 (m, 1H), 3.15-3.08 (m, 1H), 1.96-1.41 (m, 19H), 0.93 (d, J=6.8Hz, 3H). LCMS m/z 437.3 [M+H]³⁰

Example 267

9-((4-chloro-3-((trans-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 194.¹H NMR (400 MHz, CD₃OD) δ: 8.84 (s, 1H), 8.03 (s, 1H), 7.90 (d, J=8.8Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 4.65-4.58 (m, 2H), 4.03-3.95 (m, 1H),3.63-3.59 (m, 2H), 3.39-3.34 (m, 1H), 2.53-2.50 (m, 2H), 2.24-1.68 (m,12H), 1.41-1.25 (m, 3H), 1.18-1.05 (m, 2H), 0.91 (d, J=6.8 Hz, 3H).ESI-MS (M+H)⁺: 456.2.

Example 2688-(3-((cis-4-(tert-butyl)cyclohexyl)amino)isoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 195.¹H NMR (400 MHz, CD₃OD) δ: 9.08 (s, 1H), 8.12 (s, 1H), 7.82 (d, J=9.2Hz, 1H), 7.77 (d, J=9.2 Hz, 1H), 7.28 (s, 1H), 4.83 (s, 1H), 4.27-4.24(m, 1H), 4.00-3.97 (m, 1H), 3.03-2.97 (m, 1H), 2.12-1.73 (m, 14H),1.42-1.33 (m, 2H), 1.20-1.14 (m, 1H), 0.93 (s, 9H); ESI-MS (M+H)⁺:464.3.

Example 2698-(2-((cis-4-methylcyclohexyl)amino)quinazoline-6-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 192.¹H NMR (400 MHz, DMSO-d₆) δ: 9.19 (s, 1H), 8.42 (s, 1H), 7.94 (s, 1H),7.72 (d, J=8.0 Hz, 1H), 7.46-7.44 (m, 2H), 4.65-4.60 (m, 1H), 4.18-4.13(m, 1H), 4.10-4.02 (m, 1H), 2.78-2.70 (m, 1H), 1.74-1.41 (m, 17H), 0.92(d, J=6.8 Hz, 3H). LCMS m/z 423.2 [M+H]³⁰

Example 270

8-((3-((cis-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 193.¹H NMR (400 MHz, CD₃OD) δ: 8.77 (s, 1H), 7.84 (s, 1H), 7.59 (s, 2H),6.65 (s, 1H), 3.98 (s, 2H), 3.62-3.58 (m, 2H), 3.53-3.50 (m, 1H),2.62-2.59 (m, 1H), 2.28-2.25 (m, 2H), 2.13-2.11 (m, 2H), 2.15-1.98 (m,2H), 1.90-1.88 (m, 2H), 1.82-1.78 (m, 4H), 1.45-1.43 (m, 1H), 1.31-1.24(m, 2H), 1.21-1.14 (m, 2H), 0.97 (d, J=6.4 Hz, 3H); ESI-MS (M+H)⁺:408.1.

Example 2719-((4-chloro-3-((cis-4-methylcyclohexyl)amino)isoquinolin-7-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 194.¹H NMR (400 MHz, CD₃OD) δ: 8.90 (s, 1H), 8.10 (s, 1H), 7.99 (d, J=8.0Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 4.71-4.64 (m, 2H), 4.31-4.30 (m, 1H),3.68-3.65 (m, 2H), 3.45-3.40 (m, 1H), 2.58-2.56 (m, 2H), 2.31-2.06 (m,6H), 1.94-1.66 (m, 9H), 1.40-1.33 (m, 2H), 1.02 (d, J=6.4 Hz, 3H);ESI-MS (M+H)⁺: 456.2

Example 2728-(3-((cis-4-(tert-butyl)cyclohexyl)amino)-4-chloroisoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 195.¹H NMR (400 MHz, CD₃OD) δ: 8.95 (s, 1H), 8.07 (s, 1H), 7.96 (d, J=8.8Hz, 1H), 7.75 (dd, J=1.6 Hz, 9.2 Hz, 1H), 4.88 (s, 1H), 4.44-4.40 (m,1H), 4.28-4.24 (m, 1H), 3.03-2.97 (m, 1H), 2.12-1.86 (m, 10H), 1.73-1.63(m, 4H), 1.37-1.27 (m, 2H), 1.19-1.13 (m, 1H), 0.93 (s, 9H); ESI-MS(M+H)⁺: 498.1

Example 2738-(3-((trans-4-(tert-butyl)cyclohexyl)amino)-4-chloroisoquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 195.¹H NMR (400 MHz, CD₃OD) δ: 8.94 (s, 1H), 8.05 (s, 1H), 7.94 (d, J=8.8Hz, 1H), 7.74 (dd, J=1.6 Hz, 9.2 Hz, 1H), 4.83 (s, 1H), 4.28-4.25 (m,1H), 4.04-3.99 (m, 1H), 3.04-2.96 (m, 1H), 2.17-1.86 (m, 12H), 1.42-1.08(m, 5H), 0.93 (s, 9H); ESI-MS (M+H)⁺: 498.1.

Example 274 9-((8-bromo-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

The title compound was prepared according to the method of Example 197.1H NMR (400 MHz, CD₃OD) δ: 9.54 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.87(s, 1H), 7.69 (d, J=9.2 Hz, 1H), 4.93 (s, 1H), 4.70 (s, 2H), 3.63-3.60(m, 2H), 3.34-3.30 (m, 1H), 2.36-2.00 (m, 11H), 1.91-1.80 (m, 3H),1.69-1.61 (m, 5H); ESI-MS (M+H)⁺: 555.1.

Example 2758-((8-bromo-7-((cis-4-(trifluoromethyl)cyclohexyl)oxy)isoquinolin-3-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 197.¹H NMR (400 MHz, CD₃OD) δ: 9.54 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.82(s, 1H), 7.69 (d, J=8.8 Hz, 1H), 4.93 (s, 1H), 4.37 (s, 2H), 4.04-4.00(m, 2H), 2.92-2.87 (m, 1H), 2.40-2.38 (m, 2H), 2.24-2.36 (m, 9H),1.90-1.80 (m, 2H), 1.69-1.61 (m, 4H); ESI-MS (M+H)⁺: 541.1.

Example 2768-((8-bromo-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 197.¹H NMR (400 MHz, CD₃OD) δ: 9.60 (s, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.93(s, 1H), 7.74 (d, J=9.2 Hz, 1H), 4.96 (s, 1H), 4.47 (s, 2H), 4.05-4.03(m, 2H), 2.78-2.71 (m, 1H), 2.44-2.41 (m, 2H), 2.19-2.00 (m, 8H),1.73-1.51 (m, 6H), 1.38-1.29 (m, 3H), 0.94 (t, J=6.4 Hz, 3H); ESI-MS(M+H)⁺: 501.2.

Example 2778-((8-chloro-7-((cis-4-ethylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 196.¹H NMR (400 MHz, CD₃OD) δ: 9.54 (s, 1H), 7.97 (s, 1H), 7.93 (d, J=9.2Hz, 1H), 7.75 (d, J=9.2 Hz, 1H), 4.91 (s, 1H), 4.21 (s, 2H), 3.73-3.70(m, 2H), 2.64-2.61 (m, 1H), 2.30-2.28 (m, 2H), 2.12-2.03 (m, 4H),1.94-1.84 (m, 4H), 1.71-1.52 (m, 6H), 1.39-1.32 (m, 3H), 0.94 (t, J=6.4Hz, 3H); ESI-MS (M+H)⁺: 457.0.

Example 278 8-((6-((cis4-ethylcyclohexyl)oxy)quinolin-2-yl)amino)bicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 199to give the title compound as a white solid (5 mg, yield: 33%). ¹H NMR(400 MHz, CD₃OD) δ: 7.77 (d, J=9.2 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.13(dd, J=2.4 Hz, 8.8 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.86 (d, J=8.8 Hz,1H), 4.52 (s, 1H), 3.94-3.90 (m, 1H), 2.57-2.51 (m, 1H), 2.27 (m, 2H),1.94-1.77 (m, 6H), 1.57-1.47 (m, 6H), 1.37-1.19 (m, 7H), 0.83 (t, J=7.2Hz, 3H). ESI-MS (M+H)⁺: 423.3.

Example 279 9-((8-bromo-7-((cis-4-methylcyclohexyl)oxy)isoquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

The title compound was prepared according to the method of Example 197.¹H NMR (400 MHz, CD3OD) δ: 9.63 (s, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.97(s, 1H), 7.77 (d, J=9.6 Hz, 1H), 4.95 (s, 1H), 4.79 (s, 2H), 3.72-3.70(m, 2H), 3.41-3.35 (m, 1H), 2.49-2.42 (m, 4H), 2.25-1.97 (m, 7H),1.85-1.70 (m, 3H), 1.60-1.50 (m, 5H), 1.00 (d, J=6.0 Hz, 3H); ESI-MS(M+H)⁺: 501.1.

Example 2808-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)quinolin-2-yl)amino)bicyclo[3.2.1]octane-3-carboxylicacid

The title compound was prepared according to the method of Example 198to give the title compound as a white solid (10 mg, yield: 42%). ¹H NMR(400 MHz, CD₃OD, a mixture of cis and trans isomers) δ: 8.14 (d, J=8.8Hz, 1H), 7.79-7.75 (m, 1H), 7.46-7.42 (m, 1H), 7.01 (d, J=9.6 Hz, 0.3H),6.90 (d, J=9.6 Hz, 0.7H), 4.78 (s, 1H), 4.30-4.27 (m, 0.3H), 3.92-3.89(m, 0.7H), 2.64-2.45 (m, 1H), 2.36 (m, 1.4H), 2.25 (m, 0.6H), 2.06-1.85(m, 7H), 1.67-1.30 (m, 12H), 0.93 (t, J=6.8 Hz, 3H). ESI-MS (M+H)⁺:491.3.

Example 2819-((5-chloro-6-((cis-4-ethylcyclohexyl)oxy)quinolin-2-yl)amino)bicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 199and Example 196 to give the title compound as a yellow solid (15 mg,yield: 38%). ¹H NMR (400 MHz, CD₃OD, a mixture of cis and trans isomers)δ: 8.08-8.04 (m, 1H), 7.46-7.41 (m, 1H), 7.29-7.25 (m, 1H), 6.92-6.82(m, 1H), 4.57 (s, 1H), 4.16 (s, 0.4H), 3.97 (s, 0.2H), 3.70 (s, 0.4H),3.03-2.80 (m, 1H), 2.27-1.76 (m, 23H), 0.83 (t, J=7.2 Hz, 3H). ESI-MS(M+H)⁺: 471.3.

Example 282(1R,3S,5S)-9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3,7-dicarboxylicacid

To a mixture of5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalene-2-carbaldehyde(80 mg, 0.21 mmol, prepared according to the method Example 84) and9-Aza-bicyclo[3.3.1]nonane-3,7-dicarboxylic acid diethyl esterhydrochloride (94 mg, 0.31 mmol) in THF (2.0 mL) was added triethylamine(0.043 mL, 0.31 mmol), sonicated for 5 min. followed by the addition ofacetic acid (0.02 mL, 0.31 mmol) and sodium triacetoxyborohydride (87mg, 0.41 mmol), the reaction was then heated in microwave at 100° C. for10 min. LCMS showed desired intermediate formation (RT 1.64 min,MH+644.0). The reaction mixture was diluted with EtOAc and washed withbrine. The organic phase was dried over MgSO₄ and concentrated. Thecrude was then dissolved in THF (1.0 mL) and methanol (1.0 mL), treatedwith aqueous 3N NaOH (1.0 mL), the mixture was then heated in microwaveat 100° C. for 10 min. The reaction mixture was then neutralized with 2NHCl. The organic phase was dried, concentrated. The crude was purifiedby HPLC to give the title compound as a white powder (75.6 mg; yield62.8%). ¹H NMR (400 MHz, METHANOL-d4) δ 8.29 (d, J=8.53 Hz, 1H),8.08-8.22 (m, 2H), 7.74 (dd, J=1.88, 9.16 Hz, 1H), 7.60 (d, J=9.54 Hz,1H), 5.03 (br. s., 1H), 4.69 (s, 2H), 3.78 (br. s., 2H), 3.38 (br. s.,1H), 1.98-2.82 (m, 12H), 1.65-1.90 (m, 6H); 19F NMR (376 MHz,METHANOL-d4) d ppm −77.06 (br. s., 3 F, TFA) −75.57 (br. s., 3 F) −53.67(s, 3 F); ESI-MS (M+H)⁺: 588.0.

Example 2839-(1R,3S,5S,7S)-2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-azaadamantane-5-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d4) δ 8.28 (d, J=8.53 Hz, 1H), 8.07-8.20 (m,2H), 7.72 (dd, J=1.63, 9.16 Hz, 1H), 7.60 (d, J=9.29 Hz, 1H), 5.03 (br.s., 1H), 4.72 (d, J=19.33 Hz, 2H), 3.72 (d, J=6.02 Hz, 2H), 2.52-2.77(m, 2H), 1.97-2.41 (m, 11H), 1.64-1.96 (m, 7H); ESI-MS (M+H)⁺: 556.0.

Example 2849-(1R,3R,5S)-7-amino-9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d4) δ 8.28 (d, J=8.28 Hz, 1H), 8.08-8.20 (m,2H), 7.75 (dd, J=1.76, 9.04 Hz, 1H), 7.60 (d, J=9.29 Hz, 1H), 5.03 (br.s., 1H), 4.69 (s, 2H), 4.06-4.23 (m, 1H), 3.83 (br. s., 2H), 3.10 (tt,J=6.21, 12.74 Hz, 1H), 2.07-2.56 (m, 11H), 1.65-1.90 (m, 6H); ESI-MS(M+H)⁺: 559.0.

Example 285 9-((6-(bicyclo[3.1.0]hexan-3-yloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d4) δ 8.25 (d, J=8.78 Hz, 1H), 8.06-8.18 (m,2H), 7.73 (d, J=8.78 Hz, 1H), 7.54 (d, J=9.29 Hz, 1H), 4.59-4.83 (m,3H), 3.65 (d, J=13.30 Hz, 2H), 3.36-3.52 (m, 2H), 2.57 (d, J=8.03 Hz,2H), 2.40 (dd, J=7.03, 12.80 Hz, 2H), 1.82-2.35 (m, 9H), 1.36-1.49 (m,2H), 0.42-0.55 (m, 1H), 0.18 (q, J=4.18 Hz, 1H); ESI-MS (M+H)⁺: 474.0.

Example 286 8-((6-(bicyclo[3.1.0]hexan-3-yloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The title compound was prepared according to the method of Example 84.¹H NMR (400 MHz, METHANOL-d4) δ 8.21-8.30 (m, 1H), 8.11-8.18 (m, 1H),8.03-8.10 (m, 1H), 7.65-7.74 (m, 1H), 7.51-7.59 (m, 1H), 4.69-4.83 (m,2H), 4.35 (s, 2H), 4.02 (br. s., 2H), 2.97 (tt, J=6.12, 11.70 Hz, 1H),2.33-2.62 (m, 4H), 1.90-2.27 (m, 9H), 1.36-1.51 (m, 1H), 0.44-0.54 (m,1H), 0.18 (q, J=4.02 Hz, 1H); ESI-MS (M+H)⁺: 460.0.

Example 2878-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid and Example 2888-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The chiral separation of8-{1-[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propyl}-8-aza-bicyclo[3.2.1]octane-3-carboxylicacid (prepared according to the method of Example 92) gave the two titlecompounds. The chiral method is as follow: Column: 2.1×25.0 cm ChiralPakIC from Chiral Technologies (West Chester, Pa.); CO₂ co-solvent (SolventB): Acetonitrile: Methanol (3:1) with 1% isopropylamine; IsocraticMethod: 50% Co-solvent at 80 mL/min; System Pressure: 100bar; ColumnTemperature: 25° C.; Sample Diluent: Methanol:Dichloromethane (9:1). Twoisomers were obtained after the chiral separation. Since the absolutestereo chemistry is unknown, Peak#1 (chiral HPLC: RT 2.3 min.; 100% eewas randomly assigned as the R-isomer); 1H NMR (400 MHz, METHANOL-d4) δ8.34 (d, J=8.78 Hz, 1H), 8.15 (d, J=9.29 Hz, 1H), 8.03 (s, 1H), 7.71 (d,J=1.25 Hz, 1H), 7.62 (d, J=9.29 Hz, 1H), 5.03 (br. s., 1H), 4.53-4.67(m, 1H), 4.09 (dd, J=3.01, 11.55 Hz, 1H), 3.41 (d, J=6.02 Hz, 1H),2.87-3.03 (m, 1H), 1.64-2.62 (m, 19H), 0.78 (t, J=7.15 Hz, 3H); ESI-MS(M+H)⁺: 558.1; Peak#2 (chiral HPLC: RT 3.5 min.; 99.2% ee, was randomlyassigned as the S-isomer); LCMS: RT 1.57 min.; MH+ 558.0. 1H NMR (400MHz, METHANOL-d4) δ 8.34 (d, J=8.78 Hz, 1H), 8.15 (d, J=9.29 Hz, 1H),8.03 (s, 1H), 7.66-7.74 (m, 1H), 7.62 (d, J=9.29 Hz, 1H), 5.03 (br. s.,1H), 4.58 (d, J=6.02 Hz, 1H), 4.09 (dd, J=2.89, 11.42 Hz, 1H), 3.40 (br.s., 1H), 2.84-3.04 (m, 1H), 1.61-2.62 (m, 19H), 0.78 (t, J=7.28 Hz, 3H);ESI-MS (M+H)⁺: 558.0

Example 2898-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid and Example 290

8-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid

The chiral separation of8-{1-[6-(4-Ethyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-ethyl}-8-aza-bicyclo[3.2.1]octane-3-carboxylicacid (prepared according to the method of Example 88) gave the two titlecompounds. The chiral method is as follow: Column: 2.1×25.0 cm ChiralPakIC from Chiral Technologies (West Chester, Pa.); CO₂ co-solvent (SolventB): Methanol with 1% isopropylamine; Isocratic Method: 45% Co-solvent at80 mL/min; System Pressure: 100bar; Column Temperature: 25° C.; SampleDiluent: Methanol: Dichloromethane (9:1). Two isomers were obtainedafter the chiral separation. Since the absolute stereo chemistry isunknown, Peak#1 (chiral HPLC: RT 1.7 min.; 100% ee was randomly assignedas the R-isomer). ¹H NMR (400 MHz, METHANOL-d4) δ 8.30 (d, J=8.53 Hz,1H), 8.12 (d, J=9.29 Hz, 1H), 8.03 (s, 1H), 7.72 (dd, J=1.38, 9.16 Hz,1H), 7.58 (d, J=9.29 Hz, 1H), 4.95 (br. s., 1H), 4.48-4.61 (m, 1H), 4.39(q, J=6.53 Hz, 1H), 3.38-3.52 (m, 1H), 2.87-3.08 (m, 1H), 1.18-2.61 (m,22H), 0.93 (t, J=7.15 Hz, 3H); ESI-MS (M+H)⁺: 504.1; Peak#2 (chiralHPLC: RT 3.0 min.; 99.3% ee, was randomly assigned as the S-isomer). ¹HNMR (400 MHz, METHANOL-d4) δ 8.30 (d, J=8.53 Hz, 1H), 8.12 (d, J=9.29Hz, 1H), 8.04 (s, 1H), 7.72 (dd, J=1.25, 9.04 Hz, 1H), 7.57 (d, J=9.29Hz, 1H), 4.94 (br. s., 1H), 4.50-4.60 (m, 1H), 4.39 (q, J=6.53 Hz, 1H),3.39-3.52 (m, 1H), 2.87-3.10 (m, 1H), 2.46-2.63 (m, 1H), 1.88-2.43 (m,9H), 1.83 (d, J=6.53 Hz, 3H), 1.52-1.74 (m, 4H), 1.22-1.51 (m, 5H), 0.92(t, J=7.15 Hz, 3H); ESI-MS (M+H)⁺: 504.1

Example 2919-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid and Example 2929-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The chiral separation of9-{1-[6-(4-Ethyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-ethyl}-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid (prepared according to the method of Example 88) gave the two titlecompounds. The chiral method is as follow: Column: 3.0×25.0 cm (S,S)Whelk0-1 from Regis Technologies (Morton Grove, Ill.) CO₂ co-solvent(Solvent B): Acetonitrile: Methanol (3:1) with 1% isopropylamine;Isocratic Method: 35% Co-solvent at 80 mL/min; System Pressure: 100bar;Column Temperature: 25° C.; Sample Diluent: Methanol:Dichloromethane(9:1). Two isomers were obtained after the chiral separation. Since theabsolute stereo chemistry is unknown, Peak#1 (chiral HPLC: RT 1.4 min.;99.7% ee was randomly assigned as the R-isomer). ¹H NMR (400 MHz,METHANOL-d4) δ 8.29 (d, J=8.78 Hz, 1H), 8.05-8.18 (m, 2H), 7.79 (dd,J=1.88, 9.16 Hz, 1H), 7.57 (d, J=9.29 Hz, 1H), 5.00-5.27 (m, 1H), 4.94(br. s., 1H), 4.18 (br. s., 1H), 3.38 (td, J=6.18, 12.49 Hz, 1H), 3.17(d, J=13.30 Hz, 1H), 2.30-2.63 (m, 3H), 1.52-2.28 (m, 16H), 1.21-1.51(m, 5H), 0.92 (t, J=7.15 Hz, 3H); ESI-MS (M+H)⁺: 518.1; For Peak#2(chiral HPLC: RT 2.0 min.; 99.3% ee, was randomly assigned as theS-isomer). ¹H NMR (400 MHz, METHANOL-d4) δ 8.29 (d, J=8.78 Hz, 1H), 8.12(d, J=8.28 Hz, 2H), 7.78 (dd, J=1.76, 9.04 Hz, 1H), 7.57 (d, J=9.29 Hz,1H), 5.00-5.27 (m, 1H), 4.94 (br. s., 1H), 4.18 (br. s., 1H), 3.38 (td,J=6.15, 12.30 Hz, 1H), 3.17 (d, J=12.80 Hz, 1H), 2.30-2.63 (m, 3H),1.52-2.29 (m, 16H), 1.21-1.50 (m, 5H), 0.92 (t, J=7.15 Hz, 3H); ESI-MS(M+H)⁺: 518.1

Example 293 8-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid andExample 294 8-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid

The chiral separation of8-{1-[6-(4-Ethyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propyl}-8-aza-bicyclo[3.2.1]octane-3-carboxylicacid (prepared according to the method of Example 92). Two isomers wereobtained after the chiral separation. Since the absolute stereochemistry is unknown, Peak#1 (chiral HPLC: RT 2.7 min.; 100% ee wasrandomly assigned as the R-isomer); 1H NMR (400 MHz, METHANOL-d4) δ 8.32(d, J=8.53 Hz, 1H), 8.12 (d, J=9.29 Hz, 1H), 8.01 (s, 1H), 7.67 (dd,J=1.51, 9.04 Hz, 1H), 7.59 (d, J=9.29 Hz, 1H), 4.96 (br. s., 1H),4.39-4.65 (m, 1H), 4.09 (dd, J=3.01, 11.55 Hz, 1H), 3.41 (d, J=6.27 Hz,1H), 2.86-3.04 (m, 1H), 1.86-2.62 (m, 12H), 1.53-1.81 (m, 4H), 1.24-1.51(m, 5H), 0.93 (t, J=7.03 Hz, 3H), 0.78 (t, J=7.28 Hz, 3H); ESI-MS(M+H)⁺: 518.1; Peak#2 (chiral HPLC: RT 3.9 min.; 99.6% ee, was randomlyassigned as the S-isomer, 1H NMR (400 MHz, METHANOL-d4) δ 8.32 (d,J=8.53 Hz, 1H), 8.07-8.17 (m, 1H), 8.01 (s, 1H), 7.68 (dd, J=1.51, 9.04Hz, 1H), 7.59 (d, J=9.29 Hz, 1H), 4.96 (br. s., 1H), 4.36-4.65 (m, 1H),4.08 (dd, J=3.26, 11.55 Hz, 1H), 3.41 (d, J=6.02 Hz, 1H), 2.86-3.03 (m,1H), 2.48-2.62 (m, 1H), 1.86-2.48 (m, 11H), 1.53-1.75 (m, 4H), 1.22-1.52(m, 5H), 0.93 (t, J=7.15 Hz, 3H), 0.78 (t, J=7.28 Hz, 3H); ESI-MS(M+H)⁺: 518.1.

Example 2959-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid and Example 2969-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid

The chiral separation of9-{1-[5-Trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propyl}-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid (prepared according to the method of Example 92). Two isomers wereobtained after the chiral separation. Since the absolute stereochemistry is unknown, Peak#1 (chiral HPLC: RT 1.2 min.; 99.9% ee, wasrandomly assigned as the R-isomer). ¹H NMR (400 MHz, METHANOL-d4) δ 8.34(d, J=7.28 Hz, 1H), 8.04-8.21 (m, 2H), 7.76 (d, J=8.28 Hz, 1H), 7.62 (d,J=9.29 Hz, 1H), 5.03 (br. s., 1H), 4.93 (dd, J=3.51, 11.55 Hz, 1H), 4.26(d, J=11.80 Hz, 1H), 3.35-3.46 (m, 1H), 3.07-3.21 (m, 1H), 1.52-2.60 (m,21H), 0.75 (t, J=7.15 Hz, 3H); ESI-MS (M+H)⁺: 572.1; Peak#2 (chiralHPLC: RT 1.8 min.; 98.6% ee, was randomly assigned as the S-isomer. 1HNMR (400 MHz, METHANOL-d4) δ 8.34 (d, J=7.28 Hz, 1H), 8.05-8.21 (m, 2H),7.76 (d, J=8.53 Hz, 1H), 7.62 (d, J=9.29 Hz, 1H), 5.04 (br. s., 1H),4.93 (dd, J=3.76, 11.80 Hz, 1H), 4.26 (d, J=12.30 Hz, 1H), 3.39 (dd,J=5.65, 12.17 Hz, 1H), 3.08-3.21 (m, 1H), 1.54-2.60 (m, 21H), 0.75 (t,J=7.15 Hz, 3H);); ESI-MS (M+H)⁺: 572.1.

Example 2979-((R)-1-(6-(((1s,4S)-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid andExample 2989-((S)-1-(6-(((1S,4R)-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid

The chiral separation of9-{1-[6-(4-Ethyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propyl}-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid (prepared according to the method of Example 92). Two isomers wereobtained after the chiral separation. Since the absolute stereochemistry is unknown, Peak#1 (chiral HPLC: RT 1.7 min.; 100% ee) wasrandomly assigned as the R-isomer; ¹H NMR (400 MHz, METHANOL-d4) δ8.23-8.39 (m, 1H), 8.11 (br. s., 2H), 7.67-7.82 (m, 1H), 7.59 (d, J=9.29Hz, 1H), 4.96 (br. s., 2H), 4.17-4.33 (m, 1H), 3.35-3.46 (m, 1H),3.05-3.23 (m, 1H), 2.06 (d, J=11.29 Hz, 13H), 1.19-1.78 (m, 10H), 0.93(t, J=7.15 Hz, 3H), 0.75 (t, J=7.15 Hz, 3H); ESI-MS (M+H)⁺: 532.1;Peak#2 (chiral HPLC: RT 2.8 min.; 99.4% ee), was randomly assigned asthe S-isomer; 1H NMR (400 MHz, METHANOL-d4) δ 8.32 (d, J=7.28 Hz, 1H),8.01-8.18 (m, 2H), 7.75 (d, J=8.03 Hz, 1H), 7.59 (d, J=9.29 Hz, 1H),4.90-5.00 (m, 2H), 4.26 (d, J=11.80 Hz, 1H), 3.35-3.46 (m, 1H), 3.14 (d,J=14.56 Hz, 1H), 1.79-2.61 (m, 13H), 1.53-1.79 (m, 5H), 1.23-1.51 (m,5H), 0.93 (t, J=7.15 Hz, 3H), 0.75 (t, J=7.28 Hz, 3H); ESI-MS (M+H)⁺:532.1.

Example 2994-(2-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-2H-tetrazol-5-yl)piperidine

Step 1:1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propylmethanesulfonate

To a solution of1-[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol(220 mg, 0.52 mmol) and N,N-diisopropylethylamine (0.27 mL, 1.57 mmol)in methylene chloride (2 mL) was added methanesulfonyl chloride (0.081mL, 1.05 mmol) dropwise. A white precipitate formed. The solution wasstirred at rt for 5h. LCMS showed no starting material left, andcomplete conversion to RT 2.36 min. The mixture was diluted with DCM andwashed with sodium bicarbonate solution and water, dried over MgSO₄,filtered, concentrated. The residue was used as in the next step.

Step 2:4-(2-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-2H-tetrazol-5-yl)piperidine

To a solution of methanesulfonic acid1-[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propylester (0.26 g, 0.52 mmol) in N,N-dimethylformamide (2 mL),4-(1H-Tetrazol-5-yl)-piperidine (0.15980 g, 1.0432 mmol) was added,followed by Cesium Carbonate (0.51 g, 1.56 mmol). The reaction was thenheated at 60° C. for 2h and 80° C. overnight. Cooled down, the reactionmixture was diluted with EtOAc, washed with water (×3). The organicphase was then separated, dried and concentrated. The crude was purifiedby silica gel column with Heptane/ethyl acetate to give a jell (39 mg,yield 13%). ¹H NMR (400 MHz, METHANOL-d4) δ 8.17 (d, J=7.40 Hz, 1H),8.10 (d, J=9.35 Hz, 1H), 7.84-8.01 (m, 1H), 7.58-7.70 (m, 1H), 7.49-7.58(m, 1H), 6.08 (dd, J=6.84, 8.72 Hz, 0.75H), 5.80 (t, J=7.65 Hz, 0.12H),5.00 (br. s., 1H), 3.36-3.54 (m, 2H), 3.09-3.28 (m, 2H), 1.66-2.77 (m,14H), 0.95 (t, J=7.31 Hz, 3H). LCMS m/z 556.0 [M+H]⁺

Example 3009-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carbonitrile

Step 1:1-(5-(trifluoromethyl)-6-(cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethylmethanesulfonate

To a solution of1-[5]-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-ethanol(1.03 g, 2.53 mmol) and N,N-diisopropylethylamine (1.32 mL, 7.60 mmol)in methylene chloride (9.75 mL) was added methanesulfonyl chloride (0.39mL, 5.07 mmol) dropwise. A white precipitate formed. The solution wasstirred at rt for 5h. LCMS showed no starting material left, andcomplete conversion to RT 2.36 min. The mixture was diluted with DCM andwashed with sodium bicarbonate solution and water, dried over MgSO₄,filtered, concentrated. The residue was used as in the next step.

Step 2:9-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carbonitrile

To a solution of methanesulfonic acid1-[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-ethylester (0.62 g, 1.3 mmol) in N,N-dimethylformamide (5 mL),9-aza-bicyclo[3.3.1]nonane-3-carbonitrile (0.478 g, 2.56 mmol) wasadded, followed by Cesium Carbonate (1.25 g, 3.84 mmol). The reactionwas then heated at 60° C. for 2h and 80° C. overnight. Cooled down, thereaction mixture was diluted with EtOAc, washed with water (×3). Theorganic phase was then separated, dried and concentrated. The crude waspurified by silica gel column with HE/EA to give a jell (0.26 g, yield37%). ¹H NMR (400 MHz, METHANOL-d4) δ 8.35 (d, J=9.10 Hz, 1H), 8.18 (br.s., 2H), 7.80 (d, J=11.80 Hz, 1H), 7.63 (d, J=9.29 Hz, 1H), 5.24 (br.s., 1H), 5.05 (br. s., 1H), 4.24 (br. s., 1H), 3.80 (s, 1H), 3.19 (br.s., 1H), 1.52-2.88 (m, 23H). LCMS m/z 539.0 [M+H]⁺

Example 3018-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carbonitrile

To a solution of methanesulfonic acid1-[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-ethylester (0.62 g, 1.3 mmol) in N,N-dimethylformamide (5 mL),8-azabicyclo[3.2.1]octane-3-carbonitrile (0.442 g, 2.56 mmol) was added,followed by Cesium Carbonate (1.25 g, 3.84 mmol). The reaction was thenheated at 60° C. for 2h and 80° C. overnight. Cooled down, the reactionmixture was diluted with EtOAc, washed with water (×3). The organicphase was then separated, dried and concentrated. The crude was purifiedby silica gel column with HE/EA to give a jell (0.414 g, yield 62%). ¹HNMR (400 MHz, METHANOL-d4) δ 8.32 (d, J=9.10 Hz, 1H), 8.16 (s, 1H), 8.08(br. s., 1H), 7.74 (d, J=8.97 Hz, 1H), 7.61 (d, J=9.29 Hz, 1H), 5.03(br. s., 1H), 4.57 (br. s., 1H), 4.39 (br. s., 1H), 3.48 (br. s., 1H),1.89-2.70 (m, 11H), 1.60-1.88 (m, 10H). LCMS m/z 526.0 [M+H]⁺

Example 302 S1P Receptor Activity Assays

Compounds that are not specific for a particular S1P receptor can causeundesirable side effects. Accordingly, compounds are tested to identifythose that are specific. Accordingly, the test compounds are tested in acalcium mobilization assay/S1P receptor activity assay. The procedure isessentially as described in Davis et al. (2005) Journal of BiologicalChemistry, vol. 280, pp. 9833-9841, which is incorporated by referencein its entirety with the following modifications. Calcium mobilizationassays are performed in recombinant CHEM cells expressing human S1P₁,S1P₂, S1P₃, S1P₄, or S1P₅ purchased from Millipore (Billerica, Mass.).To detect free intracellular calcium, S1P₁, S1P₂, S1P₃, S1P₄, or S1P₅cells are loaded with FLIPR Calcium 4 dye from Molecular Devices(Sunnyvale, Calif.). Cells are imaged for calcium mobilization using aFLIPR^(TETRA) equipped with a 96-well dispense head.

Agonist percentage activation determinations were obtained by assayingsample compounds and referencing the E_(max) control for each receptorprofiled. Antagonist percentage inhibition determinations were obtainedby assaying sample compounds and referencing the control EC₈₀ wells foreach receptor profiled.

Calcium Flux Assay: Agonist Assay Format

Sample compounds were plated in an eight-point, four-fold dilutionseries in duplicate with a top concentration of 10 μM. Theconcentrations described here reflect the final concentration of thecompounds during the antagonist assay. During the agonist assay thecompound concentrations were 1.25 fold higher to allow for the finaldesired concentration to be achieved with further dilution by EC₈₀ ofreference agonists during the antagonist assay.

Reference agonists were handled as mentioned above serving as assaycontrol. The reference agonists were handled as described above forE_(max).

Assay was read for 180 seconds using the FLIPR^(TETRA) (This assay runadded sample compounds and reference agonist to respective wells). Atthe completion of the first “Single Addition” assay run, assay plate wasremoved from the FLIPR^(TETRA) and placed at 25° C. for seven (7)minutes.

Calcium Flux Assay: Antagonist Assay Format

Using the EC₈₀ values determined during the agonist assay, stimulatedall pre-incubated sample compound and reference antagonist (ifapplicable) wells with EC₈₀ of reference agonist. Read for 180 secondsusing the FLIPR^(TETRA) (This assay added reference agonist torespective wells-then fluorescence measurements were collected tocalculate percentage inhibition values).

With regard to S1P4 antagonist activity, the compounds of examples 58and 74 had IC₅₀ values of no greater than 100 nM. The compounds ofexamples 4, 11, and 80 had IC₅₀ values of no greater than 250 nM. Thecompounds of examples 44, 46, and 67 had IC₅₀ values of no greater than500 nM.

With regard to S1P4 agonist activity, the compound of example 62 had anIC₅₀ value of no greater than 500 nM.

Example 303 ATX Activity Measurements

ATX (Autotaxin) is a 125 KDa glycoprotein with lysophospholipase D(LPLD) activity that generates the bioactive lipid lysophosphatidic acid(LPA) from lysophosphatidylcholine (LPC). The ATX biochemical assayutilizes a FRET (fluorescence resonance energy transfer) technologyplatform. The fluorescence signal of FRET substrate FS-3 is quenched dueto intra-molecular FRET of a fluorophore to a non-fluorescing quencher(Ferguson, C. G., et al., Org Lett. 2006 May 11; 8(10): 2023-2026, whichis incorporated by reference in its entirety). ATX catalyzes thehydrolysis of the substrate which separates the dabsyl quencher from thefluorescein reporter, which becomes fluorescent. The reaction ismonitored by a SpectraMax M5 (Molecular Devices, Sunnyvale, Calif.) withat excitation wavelength 485 nm and emission wavelength 535 nm.

Reagents

Fatty acid free-BSA (Sigma A8806): 10 mg/mL in H₂O, stored at 4° C.2×ATX assay buffer: 100 mM Tris, 280 mM NaCl, 10 mM KCl, 2 mM CaCl₂, 2mM MgCl₂, pH 7.4.

Human ATX protein: expressed and purified in house. Stored at −80° C.

Substrate FS-3 (Echelon, L-2000): 100 μg in 77.74 μL H₂O (1 mM stock),stored at −20° C.

384-well flat bottom plates—Corning #3575.

Assay

Compound dilution—All compounds were provided at 10 mM in 100% DMSO. Inthe first well, 2 μL of 10 mM compound was added to 78 μL of DMSO (1:40dilution). In subsequent wells 3-fold dilution (total 10 dilutions) wereperformed.

1×ATX assay buffer was made up with a final concentration of 1 mg/mLfatty acid free-BSA using 2×ATX assay buffer, 10 mg/ml fatty acidfree-BSA and ddH₂O.

ATX protein was diluted with 1×ATX assay buffer to a concentration of1.32 μg/mL (1.32×). 38 μL was added per well to the assay plate. Thefinal concentration of ATX in the reaction as 1.0 μg/mL. 2 μL per wellof compounds was transferred to provide the desired concentration. Theplate was centrifuged, then incubated at room temperature for 30 minuteson the shaker.

FS-3 was diluted with 1×ATX assay buffer to a concentration of FS-3 of10 μM (5×). Then, 10 μL was added per well to the assay plate. The finalconcentration of FS-3 in the reaction was 2 μM. The plate wascentrifuged. The plate was kept shaking at room temperature for 2 hours.Because FS-3 substrate is light sensitive, plates were kept covered andprotected from light.

Fluorescence was measured using SpectraMax M5 (excitation at 485nm/emission at 538 nm, top read).

The compounds of examples 84, 88, 89, 90, 93, 94, 95, 97, 99, 100, 101,102, 104, 105, 110, 115, 118, 122, 124, 127, 128, 131, 132, 133, 134,135, 136, 137, 138, 139, 140, 141, 171, 173, 174, 175, 176, 177, 178,179, 180, 181, 182, 184, 185, 187, 190, 191, 194, 198, 199, 202, 204,206, 207, 209, 210, 211, 212, 213, 214, 216, 217, 218, 219, 220, 221,222, 223, 224, 225, 226, 227, 228, 229, 230, 233, 234, 235, 236, 238,239, 240, 241, 242, 244, 245, 246, 249, 250, 251, 253, 262, 280, 281,282, 283, 287, 289, 290, 291, 292, 294, 296 and 298 had an IC₅₀ of nogreater than 100 nM.

The compounds of examples 109, 111, 125, 126, 130, 146, 149, 150, 154,162, 165, 167, 172, 183, 186, 189, 201, 203, 205, 208, 231, 237, 252,272, 274, 284, 288, 295 and 297 had an IC₅₀ of no greater than 250 nM.

The compounds of examples 83, 85, 96, 106, 117, 123, 129, 144, 159, 169,170, 188, 197, 200, 215, 232, 244, 247, 248, 263, 264, 271, 279 and 293had an IC₅₀ of no greater than 500 nM.

OPC Differentiation Assay

Enriched populations of oligodendrocytes were grown from post-natal day2 (P2) female Sprague Dawley rats. The forebrain was dissected out andplaced in Hank's buffered saline solution (HBSS; Invitrogen, GrandIsland, N.Y.). The tissue was cut into 1 mm fragments and incubated at37° C. for 15 minutes in 0.01% trypsin and 10 μg/mL DNase. Dissociatedcells were plated on poly-L-lysine-coated T75 tissue culture flasks andgrown at 37° C. for 10 days in Dulbecco's modified Eagle's medium (DMEM)with 20% fetal calf serum (Invitrogen). A2B⁵⁺ OPCs were collected byshaking the flask overnight at 200 rpm and 37° C., resulting in a 95%pure population.

For the differentiation assay, 2 μM and 20 μM antagonist or the sameconcentrations of vehicle (DMSO) were applied to OPCs cultured inCNTF/T3 containing media. After a 3-day incubation, cells were lysed in80 μL lysis buffer (50 mM HEPES[4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid], pH 7.5, 150 mMNaCl, 1.5 mM MgCl₂, 1 mM ethylene glycol tetraacetic acid [EGTA], 1%Triton X-100 and 10% glycerol) for 30 minutes at 4° C. Aftercentrifugation at 14,000 g for 15 minutes, the supernatants were boiledin Laemmli sample buffer, subjected to 4-20% SDS-PAGE, and analyzed byWestern blotting with anti-MBP, anti-myelin-associated glycoprotein(MAG), or anti-beta actin antibodies. The secondary antibodies used wereanti-mouse IgG-HRP (horseradish peroxidase) and anti-rabbit IgG-HRPrespectively.

DRG-OPC Myelination Assay

Embryonic neocortical neurons are dissected from embryonic day 18 (E18)Sprague Dawley rats, and then plated on poly-D-lysine (100 μg/mL)-coatedcover slips and grown in neurobasal medium supplemented with B27(Invitrogen) for one week. A2B⁵⁺ OPCs are prepared as described aboveand then added into the cultured neocortical neurons. One day later,different concentrations of an S1P4 receptor antagonist or ATX inhibitorand control reagents are applied into the co-cultures. Fresh mediacontaining the different concentrations of an S1P4 receptor antagonistor ATX inhibitor or control compounds are supplied every three days.After ten days, co-cultures are subjected to sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE)/Western blot analyses toquantify MAG, MBP, and MOG.

Remyelination Assay in Brain Slice Culture

Approximately three to four consecutive 300 μm slices are taken from thejunction of the corpus callosum to the hippocampus in post-natal, day 17Sprague Dawley rats (Charles River, Willmington, Mass.). Slices arecultured in basal DMEM supplemented with 25% horse serum for three days,before being treated with 6 mg/mL LPC (Sigma L-4129) for a further threedays. The medium is then changed, and slices incubated with mediumcontaining an S1P4 receptor antagonist or ATX inhibitor or vehiclecontrol for a final period of three days, after which myelination isvisualized by black gold staining (Millipore, Bedford, Mass.) followingthe manufacture's protocol. Images are acquired using a Leica M420microscope (Bannockburn, Ill.) and the staining intensity of corpuscallosum is analyzed using Metamorph software (Molecular Devices,Downingtown, Pa.). Three or four brain slices are used for eachtreatment group.

Lysolecithin Demyelination Model

Adult Sprague Dawley rats (220-260 g) are anesthetized byintraperitoneal injection of a cocktail, consisting of Ketamine (35mg/kg), Xylazine (6 mg/kg) and Acepromazine (1 mg/kg). The back of theanimal is shaved from the lower thoracic to the lumbar region,subsequently sanitized with 70% isopropanol, Betadine Scrub solution,and 70% isopropanol again. The animal is then placed onto stereotaxicframe.

After ensuring an adequate anesthetic level, the skin is incised alongthe midline over the thoracic region. The dorsal fascia is incised andthe paraspinal muscles separated from the spinous processes of thethoracic vertebrae T-9 through T-11. The T-10 vertebra is demolished,and the lamina removed with micro-rongeurs. Once the dorsal spinal cordregion is exposed, a microcapillary glass needle is inserted into thedorsal column to a depth of 0.6 mm. The demyelinating reagent, 1.5 μL of1% Lysolecithin (LPC, Sigma#L1381) in saline is injected with theinfusion rate of 2 nL/sec controlled by a micro-pump (World PrecisionInstrument #micro4). Once the injection is completed, the needle isplaced for additional 1 min before removal. The paraspinal muscles andthe lumbar fascia are closed with suture (#5, silk). The skin incisionis closed with wound clips. Animals are allowed to recover from theanesthesia and are observed in the humidified incubator.

Buprenorphine (0.05 mg/kg) is administrated subcutaneously (s.c.) twicea day for additional two days following operation.

Three days following the primary surgery, treatments with an S1P4receptor antagonist or ATX inhibitor (30 pmol), LPA (30 pmol) or control(0.1% DMSO in saline) are injected at the primary injection region in avolume of 1.5 μL with the same infusion speed as indicated above. Ninedays following the primary surgery, the animals are anesthetized andperfused trans-cardially with heparin (10 iu/mL) in saline followed by4% PFA in PBS. The spinal cords are removed and post fixed in PFAovernight. Then the cords are cut into 100 μM thickness longitudinallyand then 1% loxuol fast blue is stained and histological evaluation forremyelination and repair is assessed under microscope.

For systemic treatment, the animals are administered once dailyintraperitoneally with either an S1P4 receptor antagonist or ATXinhibitor (10 mg/kg) or control (15% HPCD(hydroxypropyl-β-cyclodextrin)) 2 days following the primary surgery.Nine days after the primary surgery, animals are sacrificed and thespinal cords were processed as indicated above.

In Vivo Screening Assays

Measurement of circulating lymphocytes: Compounds are dissolved in 30%HPCD. Mice (C57bl/6 male, 6-10 week-old) are administered 0.5 and 5mg/kg of a compound via oral gavage 30% HPCD is included as a negativecontrol.

Blood is collected from the retro-orbital sinus 5 and 24 hours afterdrug administration under short isoflurane anesthesia. Whole bloodsamples are subjected to hematology analysis. Peripheral lymphocytecounts are determined using an automated analyzer (HEMAVE™ 3700).Subpopulations of peripheral blood lymphocytes are stained byfluorochrome-conjugated specific antibodies and analyzed using afluorescent activating cell sorter (FACSCALIBUR™). Three mice are usedto assess the lymphocyte depletion activity of each compound screened.

Compounds of the invention can induce full lymphopenia at times as shortas 4 hours or less to as long as 48 hours or more; for example, 4 to 36hours, or 5 to 24 hours. In some cases, a compound of formula can inducefull lymphopenia at 5 hours and partial lymphopenia at 24 hours. Thedosage required to induce lymphopenia can be in the range of, e.g.,0.001 mg/kg to 100 mg/kg; or 0.01 mg/kg to 10 mg/kg. The dosage can be10 mg/kg or less, such as 5 mg/kg or less, 1 mg/kg or less, or 0.1 mg/kgor less.

CFA Inflammatory Pain Model

In the CFA (complete Freund's adjuvant) model, adult male SD (250-300 g)rats are anesthetized with isoflurane inhalation (4.5% induction/2.0%maintenance). Heat-killed M. Tuberculosis H37 RA (non-viable) suspendedat a concentration of 1.0 mg/ml in incomplete Freund's adjuvant is used(Chondrex Inc., catalog#7008). At day 0, intradermal injection (i.d.) of100 μl of CFA (1:1 oil/saline) is slowly perfused into the right footpadof the rats. At day 1, baseline tactile allodynia test are conducted:rats that develop sensitive painful response are enrolled to the study.At day 2, rats are orally dosed once with either vehicle or ATXinhibitor, then at 2 hrs, 4 hrs, 6 hrs and 24 hrs after dosage, all ratsare tested for mechanical allodynia response.

Tactile allodynia is tested as follows. A rat is placed in an elevatedPlexiglas observation chamber (approximately 4″×6“×10”) having a wiregrid (1 cm² spacing) mesh floor under polycarbonate cages. The rat isleft to acclimate to the experimental conditions for 20 minutes beforetesting begins. After the rat is calm, tactile allodynia is assessedusing a series of von Frey filaments ranging from 2.04-28.84 g(Stoelting, Wood Dale, Ill.). Graded pressure is presented to alocalized area on the plantar surface of the paw via the use of Von Freyhairs (monofilaments which are calibrated to bend at a known pressure).A response to the VonFrey hair is recorded as the rat withdrawing thetested paw and is usually followed by lifting and licking. A series offilaments are used to determine the threshold response using theestablished “Up-Down” method. Each paw is tested 4-6 times repeatedlywith 1-2 seconds (modified from Seltzer et al., 1991) in between eachprobe to accurately assess the behavior. A sharp lifting of the paw isscored as a positive response.

Rat Model of Neuropathic Pain

Chronic Constriction Injury (CCI) Surgery: In the CCI model (Bennett andXie, Pain, 1989, which is incorporated by reference in its entirety),adult male SD (250-275 g) rats are anesthetized with isofluraneinhalation (4.5% induction/2.0% maintenance). The surgery is performedunder aseptic conditions and involves exposing the sciatic nerve at themid-thigh level. Ocular lubricant is used as needed to prevent cornealdrying. After shaving and disinfecting the skin (betadine followed by70% ethanol), a small incision is made just caudal to the bicepsfemoris. Care is taken to not disturb the sciatic nerve. The nerve isslightly elevated, and 4 loose ligatures of 4-0 chromic gut suture areinserted under the nerve, and then are loosely tied around it. Thesutures constrict the nerve but do not strangle it. Prior to insertingthe chromic gut, it is rinsed twice in sterile saline. The incision isclosed with wound clips, and rats are allowed to recover from anesthesiaon a circulating water heating pad before being returned to their homecages. In the sham controls the skin is opened, and the sciatic nerve isidentified and elevated, but no sutures are tied around the nerve. Allrats are screened for pain response around post-surgery day 7 and onlyrats with sensitive pain response are enrolled to the study.

Animals are orally dosed twice/day for 3 times/week with either vehicleor ATX inhibitor post-surgery at days 10, 12, 14, 17, 19 and 21, andanimals are also tested at the same schedule for three types ofneuropathic pain: thermal hyperalgesia, tactile allodynia andincapacitance.

(1) Plantar thermal hyperalgesia: Rats are tested for hyperalgesia usinga plantar device (Ugo Basile Inc., Cat.#37370). After acclimation to thetesting room, rats are placed on an elevated glass floor beneathinverted clear plastic cages, and a radiant heat source beneath theglass is aimed at the mid-plantar surface of the hindpaw after they haveceased all exploratory behavior. The onset of light activates a timer,which is terminated by a hindpaw withdrawal response. A cutoff time of30 seconds is used to avoid tissue damage in the absence of a response.The average withdrawal latency value of three trials from theipsilateral hindpaw is measured with at least 5-10 minutes between eachtrial to avoid any tissue damage.

(2) Tactile allodynia is tested as described above.

(3) Incapacitance: The incapacitance test measures the weight the ratplaces on each of its hindpaws. The rat is placed in a small, clearPlexiglas box (6″long x 3″wide x 4″tall). The box is tilted up and opensin the front. The rat is placed in the box so that its hindpaws are atthe back (lower) portion of the box, and the forepaws are at the front(raised) part of the box. The rat's head is at the opening in the frontof the box. The box is placed on a divided scale such that each of therat's hindpaws is on one of the two weighing pans of the scale. Theweight that the rat placed on each hindpaw is then measured. Theprocedure is rapid (about 10 sec) and does not cause the animal anypain.

Other embodiments are within the scope of the following claims.

What is claimed is:
 1. A compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X is O, or NR¹²;A¹, A², A³, A⁵, A⁶ and A⁷ are each independently CR²; “------” indicatesa double bond; R¹ is a C₆₋₂₀alkyl, a C₃₋₁₄carbocyclyl, a 3- to15-membered heterocyclyl, a C₆₋₁₀aryl, or a five- to 14-memberedheteroaryl, wherein R¹ may be optionally substituted with from one tosix independently selected R⁶; R², for each occurrence, is independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,cyano, carboxy, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,C₃₋₈halocycloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₃₋₈cycloalkoxy,C₃₋₈halocycloalkoxy, C₁₋₆alkanoyl, amino, N—(C₁₋₆alkyl)amino,N,N-di-(C₁₋₆alkyl)amino, C₁₋₆alkoxycarbonyl, C₁₋₆alkanoyloxy, carbamoyl,N—(C₁₋₆alkyl)carbamoyl, N,N-di-(C₁₋₆alkyl)carbamoyl, C₁₋₆alkylamido,mercapto, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, sulfamoyl,N—(C₁₋₆alkyl)sulfamoyl, N,N-di-(C₁₋₆alkyl)sulfamoyl, andC₁₋₆alkylsulfonamido; each R³ and each R⁴ are each independentlyhydrogen, a carboxy, C₁₋₆alkyl, or a C₂₋₆alkenyl; or R³ and R⁴ togetherwith the carbon to which they are attached are —C(═O)—, aC₃₋₈spirocycloalkyl, or a 3- to 8-membered spiroheterocycloalkyl; R⁶,for each occurrence, is independently selected from the group consistingof halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,C₆₋₁₀aryl, C₁₋₆alkoxy-C₁₋₆alkyl, and tri-(C₁₋₆alkyl)silyl; or two R⁶that are attached to the same carbon atom may form C₃₋₈spirocycloalkylor 3- to 8-membered spiroheterocycloalkyl; R⁸, and R¹² are eachindependently hydrogen or a C₁₋₆alkyl; i is an integer from 0 to 6; n isan integer from 1 to 6; and (i) m is 1; B is a ring system representedby the following formula:

 and R⁵ is CO₂H; or (ii) m is 0;

 is a ring system represented by the following formula:

wherein B is optionally further substituted by oxo, hydroxy, —NH₂,—CONH₂, or —CO₂H; and R⁵ is CO₂H.
 2. The compound according to claim 1,or a pharmaceutically acceptable salt thereof, wherein: m is 1;

 is a ring system represented by the following formula:

 and R⁵ is CO₂H.
 3. The compound according to claim 2, or apharmaceutically acceptable salt thereof, wherein:

 is a bridged ring system represented by the following formula:


4. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein: m is 0;

 is a ring system represented by the following formula:

wherein B is optionally further substituted by oxo, hydroxy, —NH₂,—CONH₂, or —CO₂H; and R⁵ is CO₂H.
 5. The compound according to claim 1,wherein the compound is represented by formula (II):

or a pharmaceutically acceptable salt thereof, wherein: A^(1b), A^(2b),A^(3b), A^(5b), and A^(6b) are CR^(2b); R^(2a) is a halo, C₁₋₆haloalkylor cyano; R^(2b), for each occurrence, is independently selected fromthe group consisting of hydrogen, halo, hydroxyl, nitro, cyano, carboxy,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈halocycloalkyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, C₃₋₈cycloalkoxy, C₃₋₈halocycloalkoxy,C₋₆alkanoyl, amino, N—(C₁₋₆alkyl)amino, N,N-di-(C₁₋₆alkyl)amino,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N-di-(C₁₋₆alkyl)carbamoyl, C₁₋₆alkylamido, mercapto, C₁₋₆alkylthio,C₁₋₆alkylsulfonyl, sulfamoyl, N—(C₁₋₆alkyl)sulfamoyl,N,N-di-(C₁₋₆alkyl)sulfamoyl, and C₁₋₆alkylsulfonamido; and —(CH₂)_(p)—R⁷is R⁵.
 6. The compound according to claim 5, or a pharmaceuticallyacceptable salt thereof, wherein R^(2b), for each occurrence, isindependently hydrogen or a halo.
 7. The compound according to claim 6,wherein the compound is represented by formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein: A^(3c) andA^(5c) are CH; R⁹ is a halo, an C₁₋₆alkyl, or a C₁₋₆haloalkyl; and R¹³and R¹⁴ are each independently hydrogen or a C₁₋₆alkyl; and—(CH₂)_(p)—R⁷ is R⁵.
 8. The compound according to claim 7, wherein thecompound is represented by formula (IIb):

or a pharmaceutically acceptable salt thereof.
 9. The compound accordingto claim 8, or a pharmaceutically acceptable salt thereof, wherein: m is0;

 is a ring system represented by the following formula:

wherein B is optionally further substituted by oxo, hydroxy, —NH₂,—CONH₂, or —CO₂H; and R⁵ is CO₂H.
 10. The compound according to claim 9,or a pharmaceutically acceptable salt thereof, wherein R^(2a) is —Cl,—CF₃ or —CHF₂.
 11. The compound according to claim 10, or apharmaceutically acceptable salt thereof, wherein R⁹ is methyl, ethyl,—CF₃ or tert-butyl.
 12. The compound according to claim 1, wherein thecompound is represented by formula (III):

or a pharmaceutically acceptable salt thereof, wherein: A^(3c) is CH;R¹⁰ and R¹¹ are each independently hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,tri-C₁₋₆alkylsilyl, or phenyl, wherein at least one of R¹⁰ or R¹¹ is nothydrogen; or R¹⁰ and R¹¹ together with the carbon to which they areattached form a C₃₋₈spirocycloalkyl or 3- to 8-memberedspiroheterocycloalkyl; and —(CH₂)_(p)—R⁷ is R⁵.
 13. The compoundaccording to claim 12, or a pharmaceutically acceptable salt thereof,wherein: m is 1;

 is a bridged ring system represented by the following formula:

 and R⁵ is CO₂H.
 14. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is trifluoromethyl, difluoromethylor monofluoromethyl.
 15. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁶ is methyl, ethyl or isopropyl. 16.The compound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein: X is NH.
 17. The compound of claim 1, wherein thecompound is selected from the group consisting of:4-(((6-(cyclohexyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid; 4-(((6-((trans-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo [2.2.2]octane-1-carboxylic acid;4-(((6-((trans-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2] octane-1-carboxylic acid;4-(((6-((trans-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-((trans-4-(tert-pentyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-((trans-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid; 4-(((6-(spiro[2.5]octan-6-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid;4-(((6-(spiro[3.5]nonan-7-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid; 4-(((6-(spiro [4.5]decan-8-yloxy)naphthalen-2-yl)methyl)amino)bicyclo [2.2.2]octane-1-carboxylicacid;4-(((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2] octane-1-carboxylic acid;4-(((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid; 4-(((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo [2.2.2]octane-1-carboxylic acid;4-(((6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-((cis-4-phenylcyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-((trans-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-((cis-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-(heptyloxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylate;4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;3-(1-((6-((cis-4-isopropylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid;3-(1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid;3-(1-((6-((4,4-dimethylcyclohexyl)oxy)quinolin-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid;3-(1-((6-(heptyloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid;3-(1-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid;3-(1-((6-((4,4-dimethylcyclohexyl)oxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid;3-((1(6-(spiro[4.5]decan-8-yloxy)naphthalen-2-yl)methyl)azetidin-3-yl)cyclohexanecarboxylicacid;4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2yl)methyl)(methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;8-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;3-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylicacid;4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylicacid;4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)amino)bicyclo[2.2.1]heptane-1-carboxylicacid;4-((6-(trans-4-(Trimethylsilyl)cyclohexyloxy)naphthalen-2-yl)methylamino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-((cis-4-(Trimethylsilyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid;4-(((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)amino)bicyclo[2.2.2]octane-1-carboxylicacid; or a pharmaceutically acceptable salt thereof.
 18. The compound ofclaim 1, wherein the compound is selected from the group consisting of:9-((6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;3-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)amino)spiro[3.5]nonane-1-carboxylicacid;9-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]-nonane-3-carboxylicacid;9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid, enantiomer 1;9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid, enantiomer 2;8-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-((5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((6-(((trans,trans)-3,5-dimethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;8-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-9-azabicyclo[.3.1]nonane-3-carboxylicacid;9-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((6-((cis-4-methylcyclohexyl)amino)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((5-Chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;4-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylicacid;N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-2-azabicyclo[1.2.3]octane-7-carboxylic acid;N-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-ylcarbonyl)-decahydroisoquinoline-5-carboxylic acid;2-(2-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-2-azabicyclo[1.2.3]octane-7-carboxylicacid;2-(2-(5-(difluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalene-2-yl)acetyl)-2-azabicyclo[1.2.3]octane-7-carboxylicacid;4-(((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)aminomethyl)bicyclo[2.2.2]octane-1-carboxylicacid;8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-naphthalene-2-yl)ethyl)-8-azabicyclo[.2.1]octane-3-carboxylicacid;8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-aza-7-oxa-bicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-7-hydroxy-9-aza-bicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 1;8-(1-(6-((cis-4-Methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 2;9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 1;8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid, enantiomer 1;9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid, enantiomer 1;9-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid, enantiomer 2;8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 1;8-(1-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 2;9-((6-((cis-4-trifluoromethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;3-(4-{[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-amino}-bicyclo[2.2.2]oct-1-yl)-carboxylicacid;2-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-2-azaspiro[3.3]heptane-6-carboxylicacid;N-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-decahydroisoquinoline-8-carboxylic acid;3-((6-((cis-4-trifluoromethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-3-azabicyclo[3.3.1]nonane-9-carboxylicacid;N-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-4-aminobicyclo[2.2.1]heptane-1-carboxylicacid;3-(5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-3-azabicyclo[3.3.0]octane-7-carboxylicacid;8-((6-((4,4-difluorocyclohexyl)oxy)-5-(trifluoromethyl)naphthalene-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-3-(azetidine-3-yl)-cyclohexane-1-carboxylicacid;N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-8-aminobicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 1;N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-8-aminobicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 2;7-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-azabicyclo[2.2.1]heptane-2-carboxylicacid;N-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-aminobicyclo[3.3.1]nonane-3-carboxylicacid;9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-9-aza-7-oxabicyclo[3.3.1]nonane-3-carboxylicacid;9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-hydroxy-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-(5-trifluoromethyl-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-ylmethyl)-7-oxo-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-((6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 1;8-(1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid, enantiomer 2;9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(1-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;8-(1-(6-((cis-4-trifluoromethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(1-(6-((cis-4-ethylcyclohexyl)oxy)-5-chloronaphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((5-Chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid; and8-((5-Chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid; or a pharmaceutically acceptable salt thereof.
 19. The compound ofclaim 1, wherein the compound is selected from the group consisting of:8-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid; 8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;8-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid; 8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[13.2.1]octane-3-carboxylicacid;9-((5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-((5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoro-methyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-(1-(5-chloro-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(1-(6-((cis-4-(1,1-difluoroethyl)cyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-(1-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-(5-cyano-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(5-cyano-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-(1-(5-cyano-6-(((1s,4s)-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((5-cyano-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid; methyl8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylate;8-((r)-1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;8-((s)-1-(6-((cis-4-methylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;8-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;9-(1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-(1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((R)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((S)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-((R)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-((S)-1-(5-chloro-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid; methyl9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate;methyl9-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-9-azabicyclo[3.3.1]nonane-3-carboxylate;8-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;8-((R)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-((S)-1-(5-chloro-6-((cis-4-ethylcyclohexyl)oxy)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid; methyl8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylate;8-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)amino)-2-naphthoyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;9-((6-(bicyclo[3.1.0]hexan-3-yloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;8-((6-(bicyclo[3.1.0]hexan-3-yloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;8-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;8-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-8-azabicyclo[3.2.1]octane-3-carboxylicacid;9-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)ethyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid; 8-((R)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;8-((S)-1-(6-((cis-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid;9-((R)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid;9-((S)-1-(5-(trifluoromethyl)-6-((cis-4-(trifluoromethyl)cyclohexyl)oxy)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylicacid; 9-((R)-1-(6-(((1s,4S)-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid;9-((S)-1-(6-(((1s,4R)-4-ethylcyclohexyl)oxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl)-9-azabicyclo[3.3.1]nonane-3-carboxylic acid; ora pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier orexcipient and a compound, or a pharmaceutically acceptable salt thereof,according to claim
 1. 21. A method of treating or reducing symptoms ofmultiple sclerosis in a mammal comprising administering to said mammalan effective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof.
 22. The method of claim 21,further comprising administering to said mammal an effective amount ofone or more drugs selected from the group consisting of: acorticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory,an antirheumatic, an immunosuppressant, an antimetabolite, animmunomodulating agent, an antipsoriatic, and an antidiabetic.
 23. Amethod of treating or reducing chronic pain in a mammal comprisingadministering to said mammal an effective amount of a compound accordingto claim 1, or a pharmaceutically acceptable salt thereof.
 24. Themethod of claim 23, wherein the chronic pain is inflammatory pain. 25.The method of claim 23, wherein the chronic pain is neuropathic pain.